Process for preparing 5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedione and salts thereof

ABSTRACT

The disclosure provides a process of making the compound of Formula I, and pharmaceutically acceptable salts thereof; and the process of making the intermediate of Formula III; wherein PG is as defined as set forth in the specification.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to European Application No.EP16382648.0, filed on Dec. 23, 2016, the entirety of which isincorporated by reference herein.

FIELD OF DISCLOSURE

The present application relates to a novel process for preparing5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione,also known as the M-IV metabolite of pioglitazone, and pharmaceuticallyacceptable salts thereof.

BACKGROUND OF THE RELATED ART

Pioglitazone is a drug marketed for use in the treatment of diabetesmellitus type 2. Pioglitazone is a potent agonist for peroxisomeproliferator-activated receptor-gamma (PPARγ) and it has been proposedfor the treatment of some neurodegenerative diseases includingAlzheimer's, Parkinson's disease, ALS and Friedreich's ataxia.Pioglitazone has been associated with unwanted side effects includingcardiovascular effects, fluid retention, weight gain and bladder cancer.High doses of pioglitazone are therefore undesirable as high systemicexposure would be likely to result in serious side effects.

Pioglitazone is a “dirty” drug which is converted to many metabolites invivo. The metabolic pathway of pioglitazone after oral administrationhas been studied in several animal species and in humans and themetabolites have been described in the literature (see e.g. Sohda et at,Chem. Pharm. Bull., 1995, 43(12), 2168-2172) and Maeshiba et al,Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). At least six metaboliteshave been identified, named M-I to M-VI. Amongst these metabolites,M-II, M-III and M-IV show some pharmacological activity but are lessactive than Pioglitazone in diabetic preclinical models.

5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionehas the following structure:

Tanis et al. (J. Med. Chem. 39(26):5053-5063 (1996)) describe thesynthesis of5-[[4-[2-[5-(I-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedioneas follows:

Tanis et al. describe that the intermediate 14 was obtained in a 27%yield by reacting compound 13 in an aqueous 37% formaldehyde at 170° C.for 6 hours. In this process,5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(compound 6 in Scheme 1) was obtained in a 2.47% overall yield.

WO 2015/150476 A1 describes the use of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione,and its pharmaceutically acceptable salts, in the treatment of centralnervous system (CNS) disorders. WO 2015/150476 A1 describes that5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionewas prepared according to the process of Tanis et al. (supra) where theintermediate corresponding to compound 14 of Tanis et al. was preparedsimilarly at 160° C. for 5 hours providing a 17% yield. The overallyield of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionewas about 1.5%.

Due to the low yield of the intermediate2-[5-(I-methoxymethoxy-ethyl)pyridine-2-yl]ethanol, the process step forpreparing this intermediate is critical for the overall yield of theproduct,5-[[4-[2-[5-(I-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione.In addition, the prior art process to obtain compound 14 is difficult toscale because the reaction is carried out in a pressure vessel at a veryhigh temperature and it is a very dirty reaction.

Accordingly, the processes described in the art afford the product5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedioneonly in a very low overall yield and, therefore, they are not suitablefor large scale synthesis. In addition, the prior art process employsCH₃OCH₂Cl, a known carcinogen, for protecting the hydroxyl group in thekey intermediate. There is a need for an improved process forsynthesizing5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione,and its pharmaceutically acceptable salts.

BRIEF SUMMARY OF THE INVENTION

The present disclosure provides an improved process for preparing acompound of Formula I:

5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione,and pharmaceutically acceptable salts thereof, collectively referred toherein as “Compounds of the Disclosure” (each is individually referredto hereinafter as a “Compound of the Disclosure”).

An aspect of the present disclosure is directed to a process forpreparing a synthetic intermediate having Formula III:

wherein PG is a protecting group. In one embodiment, PG is a silylprotecting group, tetrahydropyranyl, methoxymethyl, or benzyl. Inanother embodiment, PG is a silyl protecting group, tetrahydropyranyl,or methoxymethyl. A compound having Formula III is used in processes ofpreparing Compounds of the Disclosure.

The process of preparing a compound having Formula III comprisesreacting a compound of Formula II:

wherein PG is a protecting group and LG¹ is a leaving group,

with ethylene oxide in the presence of

(a) an alkyl lithium and a copper(I)salt, or

(b) an alkyl lithium and a Lewis acid, and

a solvent,

to give a compound of Formula III:

In one embodiment, the copper(I)salt is selected from the groupconsisting of copper(I)bromide, copper(I)chloride, and copper(I)iodide.In another embodiment, the copper(I)salt is copper(I)iodide.

In another embodiment, the Lewis acid is selected from the groupconsisting of AlBr₃, AlCl₃, FeBr₃, FeCl₃, SnCl₄, Ti(OiPr)₄, BF₃,BF₃.O(Et)₂, BBr₃, BCl₃, TiCl₄, and ZnCl₂. In another embodiment, theLewis acid is selected from the group consisting of BF₃.O(Et)₂, BBr₃,BCl₃, TiCl₄, and ZnCl₂. In another embodiment, the Lewis acid isselected from the group consisting of BF₃.O(Et)₂, BBr₃ and BCl₃.

In another embodiment, the protect group is selected from the groupconsisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl. In another embodiment, the protecting groupis selected from the group consisting of a silyl protecting group,tetrahydropyranyl, and methoxymethyl. In another embodiment, theprotecting group is a silyl protected group.

In another embodiment, the leaving group is —Br.

In another embodiment, the process of preparing a compound havingFormula III comprises reacting a compound of Formula II:

wherein PG is a protecting group and LG¹ is a leaving group,

with ethylene oxide in the presence of

(a) an alkyl lithium and a copper(I)salt, e.g., copper(I)iodide, or

(b) an alkyl lithium and a Lewis acid, e.g., BF₃.O(Et)₂, BBr₃ or BCl₃,and

a solvent,

to give a compound of Formula III:

In one embodiment, the process of preparing a compound having FormulaIII comprises reacting a compound of Formula II:

wherein PG is a protecting group selected from the group consisting of asilyl protecting group, tetrahydropyranyl, methoxymethyl, and benzyl;and

LG¹ is a leaving group,

with ethylene oxide in the presence of

(a) an alkyl lithium and a copper(I)salt, e.g., copper(I)iodide; or

(b) an alkyl lithium and a Lewis acid selected from the group consistingof BF₃.O(Et)₂, BBr₃ and BCl₃, and

a solvent,

to give a compound of Formula III:

In one embodiment, the ethylene oxide, alkyl lithium, and copper(I)salt(e.g., copper(I)iodide) or the Lewis acid (collectively referred to asthe “reagents”) are added into the reaction mixture comprising thecompound of Formula II at low temperature, e.g., at a temperature ofabout −20° C., about −25° C., about −30° C., about −35° C., about −40°C., about −45° C., about −50° C., about −55° C., about −60° C., about−65° C., about −70° C., or about −75° C. In another embodiment, thereagents are added while maintaining the temperature of the reactionmixture below −20° C. In another embodiment, the reagents are addedwhile maintaining the temperature of the reaction mixture at about <−55°C.

In another embodiment, the ethylene oxide is added into the reactionmixture after first adding the alkyl lithium. In another embodiment, theethylene oxide is added into the reaction mixture after adding the alkyllithium and the copper(I)salt, e.g., copper(I)iodide, or the Lewis acid.In another embodiment, the reaction is conducted in the presence ofalkyl lithium and copper(I)iodide. In another embodiment, the alkyllithium and copper(I)iodide are added while maintaining the reactiontemperature at about below −55° C. In another embodiment, the reactionis conducted in the presence of an alkyl lithium and a Lewis acid. Inanother embodiment, the Lewis acid is selected from the group consistingof BF₃.O(Et)₂, BBr₃ and BCl₃.

In another embodiment, the reaction mixture is allowed to warm to roomtemperature, e.g., about 20-25° C., after the addition of the reagents.In another embodiment, the reaction mixture is kept at 20° C.-25° C. forat least 4 hours. In another embodiment, the reaction mixture is kept at20° C.-25° C. for at least 6 hours. In another embodiment, the reactionmixture is kept at 20° C.-25° C. for at least 8 hours. In anotherembodiment, the reaction mixture is kept at 20° C.-25° C. for at least10 hours.

In another embodiment, the process of preparing a compound havingFormula III comprises reacting a compound of Formula II:

wherein PG is a protecting group selected from the group consisting of asilyl protecting group, tetrahydropyranyl, and methoxymethyl; and

LG¹ is a leaving group,

with ethylene oxide in the presence of an alkyl lithium andcopper(I)iodide, and

a solvent, wherein

the reaction temperature is maintained below −20° C. when adding thealkyl lithium and the copper(I)iodide into the reaction mixture,

to give a compound of Formula III:

In one embodiment of this aspect of the disclosure, the ethylene oxideis added into the reaction mixture after first adding the alkyl lithium.In another embodiment of this aspect of the disclosure, the alkyllithium and copper(I)salt, e.g., copper(I)iodide, are added whilemaintaining the reaction temperature at about <−55° C. In anotherembodiment, the reaction mixture is allowed to warm to room temperature,e.g., about 20-25° C., after the addition of the reagents. In anotherembodiment, the reaction mixture is kept at 20° C.-25° C. for at least 4hours. In another embodiment, the reaction mixture is kept at 20° C.-25°C. for at least 6 hours. In another embodiment, the reaction mixture iskept at 20° C.-25° C. for at least 8 hours. In another embodiment, thereaction mixture is kept at 20° C.-25° C. for at least 10 hours.

In one embodiment, the solvent is selected from the group consisting ofa non-polar organic solvent and polar organic solvent, or a mixturethereof. In another embodiment, the solvent is selected from the groupconsisting of a non-polar aprotic organic solvent and a polar aproticorganic solvent, or a mixture thereof. In another embodiment, thesolvent is a non-polar organic solvent. In another embodiment, thesolvent is a non-polar aprotic organic solvent. In another embodiment,the solvent is selected form the group consisting of diethyl ether andmethyl tert-butyl ether, or a mixture thereof. In another embodiment,the solvent is diethyl ether. In another embodiment, the solvent is apolar organic solvent. In another embodiment, the solvent is a polaraprotic organic solvent. In another embodiment, the solvent is selectedfrom the group consisting of tetrahydrofuran, dioxane, and DMSO, or amixture thereof. In another embodiment, the solvent is tetrahydrofuran.

Another aspect of the present disclosure is directed to a process forpreparing a compound having Formula III:

the process comprising:

(a) reacting a compound having Formula II:

with an alkyl lithium in a first solvent at a temperature to give afirst reaction mixture;

wherein:

the temperature is below −20° C.:

PG is a protecting group, e.g., a protected group selected from thegroup consisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl; and

LG¹ is a leaving group, e.g., —Br,

(b) adding a solution of ethylene oxide in a second solvent at saidtemperature to said first reaction mixture at said temperature to give asecond reaction mixture; and

(c) adding a copper(I)salt, e.g., copper(I)iodide, or a Lewis acid,e.g., BF₃.O(Et)₂, BBr₃, or BCl₃, to said second reaction mixture at saidtemperature to give a third reaction mixture comprising a compoundhaving Formula III.

Another aspect of the present disclosure is directed to a process forpreparing a compound having Formula III:

the process comprising:

(a) reacting a compound having Formula II:

with an alkyl lithium in a first solvent at a temperature to give afirst reaction mixture;

wherein:

the temperature is below −20° C.;

PG is a protecting group, e.g., a protecting group selected from thegroup consisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl; and

LG¹ is a leaving group, e.g. —Br,

(b) adding a copper(I)salt, e.g., copper(I)iodide, or a Lewis acid,e.g., BF₃.O(Et)₂, BBr₇, or BCl₃, to the first reaction mixture at saidtemperature to give a second reaction mixture; and

(c) adding a solution of ethylene oxide in a second solvent at saidtemperature to the second reaction mixture at said temperature to give athird reaction mixture comprising a compound having Formula III.

In one embodiment of these aspects of the disclosure, the temperature isbelow −55° C. In another embodiment, the third reaction mixture isallowed to warm to a temperature of 20° C.-25° C. In another embodiment,the third reaction mixture is kept at 20° C.-25° C. for at least 4hours. In another embodiment, the third reaction mixture is kept at 20°C.-25° C. for at least 6 hours. In another embodiment, the reactionmixture is kept at 20° C.-25° C. for at least 8 hours. In anotherembodiment, the third reaction mixture is kept at 20° C.-25° C. for atleast 10 hours. In another embodiment, the first solvent and the secondsolvent are each independently selected from the group consisting of anon-polar aprotic solvent and a polar aprotic solvent, or a mixturethereof. In another embodiment, the solvent is selected from the groupconsisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran,dioxane, and DMSO, or a mixture thereof. In one embodiment, the firstsolvent and the second solvent are different. In another embodiment, thefirst solvent and the second solvent are the same, such as, for example,diethyl ether.

Another aspect of the present disclosure is directed to a process,comprising combining the reactants:

(a) ethylene oxide;

(b) a compound having Formula II:

(c) an alkyl lithium; and

(c) a copper(I)salt, e.g., copper(I)iodide, or a Lewis acid, e.g.,BF₃.O(Et)₂, BBr₃, or BCl₃,

in a solvent at a temperature below −20° C.,

wherein:

PG is a protecting group, e.g., a protecting group selected from thegroup consisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl; and

LG¹ is a leaving group e.g., —Br,

to give a compound having Formula III:

In one embodiment of this aspect of the invention, the reactants arecombined in a solvent at below −55° C. In one embodiment, the alkyllithium is added to a solution of the compound having Formula II in thesolvent at the temperature to form a first reaction mixture. In anotherembodiment, a solution of the ethylene oxide in the solvent is cooled tothe temperature and added to the first reaction mixture at thetemperature to give a second reaction mixture. In one embodiment, thesolvent is selected from the group consisting of a non-polar organicsolvent and a polar organic solvent, or a mixture thereof. In anotherembodiment, the solvent is selected from the group consisting of anon-polar aprotic organic solvent and a polar aprotic organic solvent,or a mixture thereof. In another embodiment, the solvent is a non-polarorganic solvent. In another embodiment, the solvent is a non-polaraprotic organic solvent. In another embodiment, the solvent isdiethylether or tert-butyl methyl ether. In another embodiment, thesolvent is a polar organic solvent. In another embodiment, the solventis a polar aprotic organic solvent. In another embodiment, the solventis selected from the group consisting of tetrahydrofuran, dioxane, andDMSO, or a mixture thereof.

In one embodiment, the copper(I)salt, e.g., copper(I)iodide, or Lewisacid, e.g., BF₃.O(Et)₂, BBr₃, or BCl₃, is added to the second reactionmixture at the temperature to give a third reaction mixture. In anotherembodiment, copper(I)iodide is added to the second reaction mixture atthe temperature to give a third reaction mixture. In another embodiment,the third reaction mixture is allowed to warm to a temperature of 20°C.-25° C. In another embodiment, the third reaction mixture is kept at20° C.-25° C. for at least 4 hours, for at least 6 hours, for at least 8hours, or for at least 10 hours.

In another embodiment, the copper(I)salt, e.g., copper(I)iodide, or theLewis acid, e.g., BF₃.O(Et)₂, BBr₃, or BCl₃, is added to the firstreaction mixture at the temperature to give a fourth reaction mixture.In another embodiment, copper(I)iodide is added to the first reactionmixture at the temperature to give a fourth reaction mixture. In anotherembodiment, a solution of the ethylene oxide in the solvent is cooled tothe temperature and added to the fourth reaction mixture at thetemperature to give a fifth reaction mixture. In another embodiment, thefifth reaction mixture is allowed to warm to a temperature of 20° C.-25°C. In another embodiment, the reaction mixture is kept at 20° C.-25° C.for at least 4 hours. In another embodiment, the reaction mixture iskept at 20° C.-25° C. for at least 6 hours. In another embodiment, thereaction mixture is kept at 20° C.-25° C. for at least 8 hours. Inanother embodiment, the reaction mixture is kept at 20° C.-25° C. for atleast 10 hours.

Another aspect of the present disclosure is directed to a process forpreparing an intermediate having Formula III:

wherein PG is a protecting group selected from the group consisting of asilyl protecting group, tetrahydropyranyl, or methoxymethyl, saidprocess comprising reacting a compound of Formula II:

wherein PG is as defined above and LG¹ is a leaving group, with ethyleneoxide in the presence of (a) an alkyl lithium and copper(I)iodide or (b)an alkyl lithium and a Lewis acid selected from the group consisting ofBF₃.O(Et)₂ (boron trifluoride etherate), BBr₃ and BCl₃, and a solvent,wherein the reaction temperature is maintained below −20° C. to give thecompound of Formula III. Preferably, PG is selected from a silylprotecting group.

In another embodiment, the process further comprises isolating saidcompound of Formula III and optionally purifying the isolated compoundof Formula III.

Another aspect of the disclosure is drawn to a process for preparing acompound of Formula IV:

comprising reacting the compound of Formula III:

wherein PG is as defined above, with R¹—Cl, wherein R¹ is anorganosulfonate, in the presence of a first base.

In another aspect, the disclosure is drawn to a process of preparing acompound of Formula V:

wherein PG is as defined above, comprising reacting the compound ofFormula IV with 4-hydroxybenzaldehyde having the structure

in the presence of a second base, such as an alkali metal carbonate, andoptionally a solvent.

In another aspect, the disclosure is drawn to a process of preparing acompound of Formula VI:

wherein PG is as defined above, comprising reacting the compound ofFormula V with 2,4-thiazolidinedione of formula

in the presence of piperidine and optionally a solvent, such as analcohol, and optionally an organic acid. Preferably, this reaction inconducted in the presence of piperidine and a solvent, and optionally anorganic acid.

In another aspect, the disclosure is directed to a process of preparinga compound of Formula VII:

wherein PG is as defined above, comprising reducing the compound ofFormula VI.

In another aspect, the disclosure is directed to a process for preparinga compound of Formula I:

or a pharmaceutically acceptable salt thereof, comprising de-protectingthe compound of Formula VII and optionally further treating with an acidto form a salt.

In one embodiment, the process further comprises isolating said compoundof Formula I, or a pharmaceutically acceptable salt thereof, andoptionally purifying the isolated compound of Formula I, or apharmaceutically acceptable salt thereof. In another embodiment, theprocess further comprises precipitating the compound of Formula I, or apharmaceutically acceptable salt thereof. In one embodiment, theprecipitation is conducted by treating the reaction mixture with a polaraprotic solvent, such as acetonitrile, at an elevated temperature, suchas at reflux temperature, and then allowing the reaction mixture to coolto room temperature. In another embodiment, the process furthercomprises isolating the precipitate comprising the compound of FormulaI, or a pharmaceutically acceptable salt thereof. In one embodiment, theprecipitate is isolated by filtration. In another embodiment, theisolated precipitate is further purified by, e.g., washing with thesolvent used in the precipitation or an aqueous mixture thereof.

In another embodiment, the process further comprises deuterating thecompound of Formula I, or a pharmaceutically acceptable salt thereof. Inanother embodiment, the isolated compound of Formula I, or apharmaceutically acceptable salt thereof, is deuterated.

In another aspect, the disclosure is directed to a compound of FormulaIII obtained by a process described herein by reacting the compound ofFormula II.

In another aspect, the disclosure is directed to a compound of Formula Iobtained by any process described herein.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

A number of attempts have been made by the inventors to find a route forsynthesizing5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione,as well as the intermediate of Formula III as defined below, in acommercial scale, obtaining an improved overall yield of5-[[4-[2-[5-(I-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione.It has now been discovered that Compounds of the Disclosure can besynthetized in a simple process applicable for large scale and affordingthe product in a high purity and an improved overall yield.

The present disclosure provides a process for preparing the syntheticintermediate of Formula III having the structure:

wherein PG is a protecting group, said process comprises reacting acompound of Formula II:

wherein PG is a protecting group and LG¹ is a leaving group,

with ethylene oxide in the presence of

(a) an alkyl lithium and a copper(I)salt, or

(b) an alkyl lithium and a Lewis acid, and

a solvent,

to give a compound of Formula III:

In one embodiment, PG is a silyl protecting group, tetrahydropyranyl,methoxymethyl, or benzyl. In another embodiment, PG is silyl protectinggroup, tetrahydropyranyl, or methoxymethyl. In another embodiment, PG isa silyl protecting group.

In one embodiment, the copper(I)salt is selected from the groupconsisting of copper(I)bromide, copper(I)chloride, and copper(I)iodide.In another embodiment, the copper(I)salt is copper(I)iodide.

In another embodiment, the Lewis acid is selected from the groupconsisting of AlBr₃, AlCl₃, FeBr₃, FeCl₃, SnCl₄, Ti(OiPr)₄, BF₃,BF₃.O(Et)₂, BBr₃, BCl₃, TiCl₄, and ZnCl₂. In another embodiment, theLewis acid is selected from the group consisting of BF₃.O(Et)₂, BBr₃,BCl₃, TiCl₄, and ZnCl₂. In another embodiment, the Lewis acid isselected from the group consisting of BF₃.O(Et)₂, BBr₃ and BCl₃.

In another embodiment, the leaving group (LG¹) is —Br.

In another embodiment, the process comprises an alkyl lithium andcopper(I)iodide.

The present disclosure provides a process for preparing the syntheticintermediate of Formula III having the structure:

wherein PG is a protecting group, said process comprises reacting acompound of Formula II:

wherein PG is a protecting group and LG is a leaving group,

with ethylene oxide in the presence of

(a) an alkyl lithium and a copper(I) salt, e.g., copper(I)iodide; or

(b) an alkyl lithium and a Lewis acid, e.g., BF₃.O(Et)₂, BBr₃ or BCl₃,and

a solvent,

to give a compound of Formula III:

In another embodiment, PG is a protecting group selected from the groupconsisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl. In another embodiment, PG is a protectinggroup selected from the group consisting of a silyl protecting group,tetrahydropyranyl, and methoxymethyl.

In one embodiment, the reagents, i.e., the ethylene oxide, alkyllithium, and copper(I)salt, e.g., copper(I)iodide, or the Lewis acid,are added into the reaction mixture comprising the compound of FormulaII at low temperature, e.g., at a temperature of about −20° C., about−25° C., about −30° C., about −35° C., about −40° C., about −45° C.,about −50° C., about −55° C., about −60° C., about −65° C., about −70°C., or about −75° C. In another embodiment, the reagents are added whilemaintaining the temperature of the reaction mixture below −20° C. Inanother embodiment, the reagents are added while maintaining thetemperature of the reaction mixture at about <−55° C. In anotherembodiment, the reagents are added to the reaction mixture at about<−55° C.

In another embodiment, the ethylene oxide is added into the reactionmixture after first adding the alkyl lithium. In another embodiment, theethylene oxide is added into the reaction mixture after adding the alkyllithium and the copper(I)salt, e.g., copper(I)iodide, or the Lewis acid.In another embodiment, the reaction mixture is allowed to warm to roomtemperature, e.g., about 20-25° C., after the addition of the reagents.In another embodiment, the reaction mixture is kept at 20° C.-25° C. forat least 4 hours, for at least 6 hours, or for at least 8 hours. Inanother embodiment, the reaction mixture is kept at 20° C.-25° C. for atleast 10 hours.

In one embodiment of this aspect of the disclosure, the reaction isconducted in the presence of an alkyl lithium and a copper(I)salt. Inanother embodiment, the reaction is conducted in the presence of analkyl lithium and copper(I)iodide. In another embodiment, the reactionis conducted in the presence of an alkyl lithium and a Lewis acid. Inanother embodiment, the reaction is conducted in the presence of analkyl lithium and a Lewis acid selected from the group consisting ofBF₃.O(Et)₂, BBr₃ and BCl₃.

In another embodiment, the process of the disclosure comprises reactinga compound of Formula II:

wherein PG is a protecting group selected from the group consisting of asilyl protecting group, tetrahydropyranyl, and methoxymethyl, and

LG¹ is a leaving group,

with ethylene oxide in the presence of an alkyl lithium andcopper(I)iodide, and

a solvent, wherein

the reaction temperature is maintained below −20° C. when adding thealkyl lithium and the copper(I)iodide into the reaction mixture,

to give a compound of Formula III:

In one embodiment, the ethylene oxide is added into the reaction mixtureafter first adding the alkyl lithium. In another embodiment, theethylene oxide is added to the reaction mixture while maintaining thereaction temperature below −20° C. In another embodiment, the alkyllithium and copper(I)salt, e.g., copper(I)iodide are added whilemaintaining the temperature of the reaction mixture below −55° C. Inanother embodiment, the ethylene oxide is added to the reaction mixturewhile maintaining the reaction temperature below −55° C. In anotherembodiment, the reaction mixture is allowed to warm to room temperature,e.g., about 20-25° C., after the addition of the reagents. In anotherembodiment, the reaction mixture is kept at 20° C.-25° C. for at least 4hours, for at least 6 hours, or for at least 8 hours. In anotherembodiment, the reaction mixture is kept at 20° C.-25° C. for at least10 hours.

In one embodiment, the solvent is selected from the group consisting ofa non-polar organic solvent and a polar organic solvent, or a mixturethereof. In another embodiment, the solvent is selected from the groupconsisting of a non-polar aprotic organic solvent and a polar aproticorganic solvent, or a mixture thereof. In another embodiment, thesolvent is a non-polar organic solvent. In another embodiment, thesolvent is a non-polar aprotic organic solvent. In another embodiment,the solvent is diethyl ether or methyl tert-butyl ether. In anotherembodiment, the solvent is a polar organic solvent. In anotherembodiment, the solvent is a polar aprotic organic solvent. In anotherembodiment, the solvent is selected from the group consisting oftetrahydrofuran, dioxane, and DMSO, or a mixture thereof.

In another embodiment, the process of the disclosure provides a processfor preparing a compound having Formula III:

the process comprising:

(a) reacting a compound having Formula II:

with an alkyl lithium in a first solvent at a temperature to give afirst reaction mixture;

wherein:

the temperature is below −20° C.;

PG is a protecting group, e.g., a protecting group selected from thegroup consisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl; and

LG¹ is a leaving group, e.g., Br,

(b) adding a solution of ethylene oxide in a second solvent at saidtemperature to said first reaction mixture at said temperature to give asecond reaction mixture; and

(c) adding a copper(I)salt, e.g., copper(I)iodide, or a Lewis acid,e.g., BF₃.O(Et)₂, BBr₃, or BCl₃, to said second reaction mixture at saidtemperature to give a third reaction mixture comprising a compoundhaving Formula III.

In another embodiment, the process of the disclosure provides a processfor preparing a compound having Formula III:

the process comprising:

(a) reacting a compound having Formula II:

with an alkyl lithium in a first solvent at a temperature to give afirst reaction mixture,

wherein:

the temperature is below −20° C.;

PG is a protecting group, e.g., a protecting group selected from thegroup consisting of a silyl protecting group, tetrahydropyranyl, andmethoxymethyl; and

LG¹ is a leaving group,

(b) adding a copper(I)salt, e.g., copper(I)iodide, or a Lewis acid,e.g., BF₃.O(Et)₂, BBr₃, or BCl₃, to the first reaction mixture at saidtemperature to give a second reaction mixture; and

(c) adding a solution of ethylene oxide in a second solvent at saidtemperature to the second reaction mixture at said temperature to give athird reaction mixture comprising a compound having Formula III.

In one embodiment of these aspects of the disclosure, the temperature isbelow −55° C. In another embodiment, the third reaction mixture isallowed to warm to a temperature of 20° C.-25° C. In another embodiment,the third reaction mixture is kept at 20° C.-25° C. for at least 4hours. In another embodiment, the third reaction mixture is kept at 20°C.-25° C. for at least 6 hours. In another embodiment, the reactionmixture is kept at 20° C.-25° C. for at least 8 hours. In anotherembodiment, the third reaction mixture is kept at 20° C.-25° C. for atleast 10 hours. In one embodiment, the first solvent and the secondsolvent are different. In another embodiment, the first solvent and thesecond solvent are the same, such as, for example, diethyl ether.Suitable solvents are those described above. In another embodiment, LG¹is bromide, i.e., —Br.

In another embodiment, the first solvent is selected from the groupconsisting of a non-polar aprotic solvent and a polar aprotic solvent,or a mixture thereof. In one embodiment, the first solvent is anon-polar aprotic solvent. In another embodiment, the first solvent isselected from the group consisting of diethyl ether and methyltert-butyl ether, or a mixture thereof. In another one embodiment, thefirst solvent is a polar aprotic solvent. In another embodiment, thefirst solvent is selected from the group consisting of THF, dioxane, andDMSO, or a mixture thereof.

In another embodiment, the second solvent is selected from the groupconsisting of a non-polar aprotic solvent and a polar aprotic solvent,or a mixture thereof. In one embodiment, the second solvent is anon-polar aprotic solvent. In another embodiment, the second solvent isselected from the group consisting of diethyl ether and methyltert-butyl ether, or a mixture thereof. In another one embodiment, thesecond solvent is a polar aprotic solvent. In another embodiment, thesecond solvent is selected from the group consisting of THF, dioxane,DMSO, and a mixture thereof.

In another embodiment, the first solvent and the second solvent are eachindependently selected from the group consisting of a non-polar aproticsolvent and a polar aprotic solvent, or a mixture thereof. In anotherembodiment, the first solvent and the second solvent are different. Inanother embodiment, the first solvent and the second solvent are thesame solvents. In another embodiment, both the first solvent and thesecond solvent are diethyl ether. In another embodiment, the processfurther comprises isolating the compound having Formula II.

In another embodiment, the process of the disclosure provides to aprocess, comprising

combining the reactants:

(a) ethylene oxide;

(b) a compound having Formula II:

(c) an alkyl lithium; and

(d) a copper(I) salt, e.g., copper(I)iodide, or a Lewis acid, e.g.,BF₃.O(Et)₂, BBr₃, or BCl₃,

in a solvent at a temperature below −20° C.,

wherein:

PG is a protecting group, e.g., a protecting group selected from thegroup consisting of a silyl protecting group, tetrahydropyranyl,methoxymethyl, and benzyl; and

LG¹ is a leaving group,

to give a compound having Formula III:

The term “reactant” or “reagent” as used herein refers to a substancethat takes part in and/or undergoes change during a chemical reaction.

In the processes described herein, reactants can be combined in anyorder that provides Formula III in an acceptable yield and purity.Reactants can also be combined as is or as a solution. For example, asolvent can be added to ethylene oxide to form a solution, and thissolution can be added to another reactant.

In one embodiment of this aspect of the invention, the reactants arecombined in a solvent below −55° C. In one embodiment, the alkyl lithiumis added to a solution of the compound having Formula II in the solventat the temperature to form a first reaction mixture. In anotherembodiment, a solution of the ethylene oxide in the solvent is cooled tothe temperature and added to the first reaction mixture at thetemperature to give a second reaction mixture. In one embodiment, thesolvent is selected from the group consisting of a non-polar aproticorganic solvent and a polar aprotic organic solvent, or a mixturethereof. In another embodiment, the solvent is a non-polar aproticorganic solvent. In another embodiment, the solvent is selected from thegroup consisting of diethyl ether and methyl tert-butyl ether, or amixture thereof. In another embodiment, the solvent is a polar aproticorganic solvent. In another embodiment, the solvent is selected from thegroup consisting of tetrahydrofuran, dioxane, and DMSO, or a mixturethereof.

In one embodiment, the copper(I)salt, e.g., copper(I)iodide, or Lewisacid, e.g., BF₃.O(Et)₂, BBr₃, or BCl₃, is added to the second reactionmixture at the temperature to give a third reaction mixture. In anotherembodiment, copper(I)iodide is added to the second reaction mixture atthe temperature to give a third reaction mixture. In another embodiment,the third reaction mixture is allowed to warm to a temperature of 20°C.-25° C. In another embodiment, the third reaction mixture is kept at20° C.-25° C. for at least 4 hours. In another embodiment, the thirdreaction mixture is kept at 20° C.-25° C. for at least 6 hours. Inanother embodiment, the third reaction mixture is kept at 20° C.-25° C.for at least 8 hours. In another embodiment, the third reaction mixtureis kept at 20° C.-25° C. for at least 10 hours.

In another embodiment, the copper(I)salt, e.g., copper(I)iodide, or theLewis acid, e.g., BF₃.O(Et)₂, BBr₃, or BCl₃ is added to the firstreaction mixture at the temperature to give a fourth reaction mixture.In another embodiment, copper(I)iodide is added to the first reactionmixture at the temperature to give a fourth reaction mixture. In anotherembodiment, a solution of the ethylene oxide in the solvent is cooled tothe temperature and added to the fourth reaction mixture at thetemperature to give a fifth reaction mixture. In another embodiment, thefifth reaction mixture is allowed to warm to a temperature of 20° C.-25°C. In another embodiment, the fifth reaction mixture is kept at 20°C.-25° C. for at least 4 hours. In another embodiment, the fifthreaction mixture is kept at 20° C.-25° C. for at least 6 hours. Inanother embodiment, the fifth reaction mixture is kept at 20° C.-25° C.for at least 8 hours. In another embodiment, the fifth reaction mixtureis kept at 20° C.-25° C. for at least 10 hours. In another embodiment,LG¹ is —Br.

In another embodiment, the present disclosure provides a process forpreparing the key intermediate used in the process of preparingCompounds of the Disclosure, having Formula III:

wherein PG is a protecting group selected from silyl protecting groups,tetrahydropyranyl, or methoxymethyl, said process comprising reacting acompound of Formula I1 having the structure:

wherein PG is a as defined above and LG¹ is a leaving group, withethylene oxide in the presence of (a) an alkyl lithium andcopper(I)iodide or (b) an alkyl lithium and a Lewis acid selected fromthe group consisting of BF₃.O(Et)₂, BBr₃ and BCl₃, and a solvent,wherein the reaction temperature is maintained below −20° C. to give thecompound of Formula III.

In one embodiment, PG is selected from silyl protecting groups. Inanother embodiment, PG is an alkyl or aryl silyl group, or a combinationthereof. In another embodiment, PG is a trialkylsilyl group. In anotherembodiment, PG is selected from the group consisting oftert-butyldimethylsilyl (TBDMS), trimethylsilyl (TMS), triethylsilyl(TES), tert-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS). Inanother embodiment, PG is tert-butyldimethylsilyl (TBDMS).

In another embodiment, PG is tetrahydropyranyl. In another embodiment,PG is methoxymethyl. In another embodiment, PG is benzyl. Preferably, PGis a silyl protecting group.

Suitable leaving groups for LG¹ include chloride (—Cl), bromide (—Br),iodide (—I), and fluoride (—F). Preferably, LG¹ is bromide.

The solvent used in this reaction can be a non-polar or polar organicsolvent. In one embodiment, the solvent is a non-polar or polar aproticorganic solvent. In one embodiment, the solvent is a non-polar aproticsolvent selected from ethers, such as, for example, diethylether andmethyl tert-butyl ether. In another embodiment, the solvent is a polaraprotic solvent, such as, for example, tetrahydrofuran (THF). In anotherembodiment, the polar aprotic solvent is dioxane or dimethyl sulfoxide(DMSO).

In one embodiment, the reaction is conducted in the presence of an alkyllithium and a copper(I)salt, e.g., copper(I)iodide, copper(I)bromide, orcopper(I)chloride. In another embodiment, the reaction is conducted inthe presence of an alkyl lithium and copper(I)iodide. In anotherembodiment, the alkyl lithium is C₁₋₆ alkyl lithium. In anotherembodiment, the alkyl lithium is selected from the group consisting ofn-butyllithium (n-BuLi), sec-butyllithium (sec-BuLi), and hexyllithium(HxLi). A suitable molar ratio of the alkyl lithium and copper(I)iodideused in the reaction is from about 8:1 to about 2:1. In one embodiment,the molar ratio of the alkyl lithium and copper(I)iodide is about 2:1.In one embodiment, the complexed copper is removed after the reaction bywashing with 10% ammonia.

In another embodiment, the reaction is conducted in the presence of analkyl lithium and a Lewis acid. In another embodiment, the reaction isconducted in the presence of an alkyl lithium and a Lewis acid selectedfrom the group consisting of BF₃.O(Et)₂, BBr₃ and BCl₃. In anotherembodiment, the Lewis acid is BF₃.O(Et)₂. Suitable alkyl lithiumcompounds are described above.

In one embodiment, the reaction temperature, i.e., the temperature ofthe reaction mixture, to form the compound of Formula III is maintainedat low temperatures, such as from about −20° C. to about −85° C., whenadding the reagents into the reaction mixture comprising the compound odFormula II, followed by stirring at room temperature, e.g., about 20-25°C. In another embodiment, the addition to the reaction mixture isconducted at a temperature of from about −40° C. to about −70° C. Inanother embodiment, the addition to the reaction mixture is conducted ata temperature of from about −50° C. to about −65° C. In anotherembodiment, the reaction temperature is maintained below about −55° C.when adding the reagents

In one embodiment, the reaction time to form the compound of Formula IIIfrom a compound of Formula II is at least 24 hours. In anotherembodiment, the reaction times to form the compound of Formula III froma compound of Formula II are from about 24 to about 40 hours, or about27 hours, or about 30 hours, or about 36 hours.

After the reaction to form the compound of Formula III from the compoundof Formula II is complete, the compound of Formula III is isolated fromthe reaction mixture and preferably purified, for example, by columnchromatography or re-crystallization, and preferably by columnchromatography, such as HPLC. The compound of Formula III can beobtained in a good yield with high purity. In certain aspects of thedisclosure, the inventors have obtained the compound of Formula IIIusing the process described above at about 95% yield and about 80%purity. In certain aspects of the disclosure, the inventors haveobtained the compound of Formula III using the process described aboveat about 50% yield and about 99% purity.

The process of the disclosure further comprises reacting the compound ofFormula III with R¹—Cl, wherein R¹ is an organosulfonate, such as atosyl group (Ts) or a mesyl group (Ms), in the presence of a first baseto give a compound of Formula IV:

wherein PG and R¹ are as defined above. The first base can be, forexample, one or more of an amine, a quaternary ammonium salt incombination with a water solution of an alkalimetal hydroxide,tetrabutylammoniumhydroxide, or an alkalimetal hydroxide. In oneembodiment, the first base is an amine. Suitable amines include, forexample, trialkylamine, such as triethylamine, and pyridine. In anotherembodiment, the first base is a quaternary ammonium salt, such astetra-n-butylammonium bromide or tetra-n-butylammonium fluoride incombination with a water solution of an alkalimetal hydroxide. Suitablealkalimetal hydroxides include NaOH and KOH. In another embodiment, thefirst base is tetrabutylammoniumhydroxide. In another embodiment, thefirst base is tetra-n-butylammonium bromide in aqueous alkalimetalhydroxide solution. In another embodiment, the first base istetra-n-butylammonium bromide in 30% NaOH.

In another embodiment, R¹—Cl is used in an amount of from about 1equivalent to about 1.50 equivalents. In another embodiment, R¹—Cl isp-Ts-Cl in an amount of from 1 equivalent to about 1.1 equivalents.

Advantageously, the reaction to prepare the compound of Formula IV isconducted in the presence of a solvent, such as, for example, toluene orDCM. In one embodiment, the solvent is toluene.

In another embodiment, the reaction to prepare the compound of FormulaIV is obtained by reacting p-Ts-Cl (about 1 eq to about 1.1 eq) with thecompound of Formula M in the presence of toluene, 30% aqueous NaOH andtetra-n-butylammonium bromide.

In one embodiment, the reaction for preparing the compound of Formula IVis conducted at a temperature of from about 15° C. to about 30° C., andpreferably at a temperature of from about 20° C. to about 25° C., andpreferably at about 20° C.

In one embodiment, the reaction times to form the compound of Formula IVfrom the compound of Formula III are from about 5 to about 26 hours, orfrom about 10 to about 26, or from about 15 to about 25 hours, or about22 hours.

The process of the disclosure further comprises reacting the compound ofFormula IV with 4-hydroxybenzaldehyde:

in the presence of a second base and a solvent to give a compound ofFormula V

wherein PG is as defined above. Suitable second bases include, forexample, alkali metal carbonates (such as potassium carbonate (K₂CO₃)),trialkylamines (such as triethylamine (Et₃N)), and alkali metalalkoxides (such as potassium tert-butoxide (KOtBu)). In one embodiment,the second base is K₂CO₃. Advantageously, the amount of the second baseis from about 1 eq to about 2 eq, and preferably about 1 eq.

In one embodiment, the solvent is selected from the group consisting oftoluene, ethanol, 2-propanol, THF, 2-MeTHF, and water, or combinationsthereof. In another embodiment, the solvent is a mixture of toluene andethanol. In another embodiment, the solvent is a mixture of toluene andethanol in a ratio of about 6:4.

In one embodiment, the reaction for preparing the compound of Formula Vis conducted at a temperature of from about 50° C. to about 80° C., andpreferably at about 80° C.

In one embodiment, additional water is added to the reaction mixture. Inone embodiment, the amount of water added is from about 2% to about 7%v/v (i.e., the volume of water relative to the volume of solvents used).In another embodiment, water is added in an amount of about 4% v/v,about 5% v/v, or about 6% v/v. In another embodiment, water is added inan amount of 5% v/v. In another embodiment, the temperature of thereaction is mixture is from about 20° C. to about 30° C. In anotherembodiment, water is added at about 20° C.

In one embodiment, the reaction times to form the compound of Formula Vfrom the compound of Formula IV are from about 6 to about 24 hours, orfrom about 10 to about 22 hours, or about 16 hours, or about 18 hours.

In another embodiment, the process comprises isolating and purifying thecompound of Formula V. In one embodiment, the purifying is performed byextraction. In another embodiment, the purifying comprises extractingwith an aqueous bisulfite solution. In another embodiment, the purifyingcomprises extracting a solution comprising the compound of Formula V andethanol with an aqueous bisulfite solution comprising ethanol;separating the aqueous phase; extracting the aqueous phase with amixture of toluene and heptane wherein the pH of the mixture is adjustedto pH 12:separating the organic layer; and recovering said purifiedcompound of Formula V. In one embodiment, the pH is adjusted to pH 12 byaddition of aqueous NaOH.

The process of the present disclosure further comprises reacting thecompound of Formula V with 2,4-thiazolidinedione:

in the presence of piperidine and optionally a solvent, and optionallyan organic acid, to give a compound of Formula VI:

wherein PG is as defined above.

In one embodiment, the reaction to form a compound of Formula VI iscarried out in the presence of piperidine and a solvent, and optionallyan organic acid. Suitable solvents in this reaction include toluene,lower alcohols (such as methanol and ethanol), hexane, cyclohexane, andmixtures thereof. In one aspect, the solvent is toluene or methanol, ora mixture thereof. Advantageously, the solvent is methanol.

In one embodiment, the reaction is carried out in the presence of anorganic acid. Suitable organic acids include carboxylic acids, such as,for example, (C₁₋₁₂)alkyl carboxylic acids (e.g., acetic acid), formicacid, and benzoic acid. In another embodiment, the reaction is carriedout without an organic acid.

Suitable reaction temperatures for obtaining the compound of Formula VIdepend on the solvent used in the reaction. For example, suitablereaction temperature can vary within the range of from about 45° C. toabout 80° C. Preferably, the reaction temperature is about 47° C. whenthe solvent is methanol. Preferably, the reaction temperature is about78° C. when the solvent is toluene. The reaction time varies dependingon the solvent and can be from about 5 hours to about 37 hours, or fromabout 9 to about 25 hours.

In another embodiment, the reaction to form the compound of Formula VIis carried out in the absence of a solvent, at a temperature which issufficiently high to cause at least partial melting of the reactionmixture. A preferred such temperature is in the range of from 100° C. to250° C., and especially from 140° C. to 200° C.

Preferably, the reaction to form the compound of Formula VI is carriedout in the presence of a solvent, and optionally an organic acid.

The process of the present disclosure further comprises reducing thecompound of Formula VI to give a compound of Formula VII:

wherein PG is as defined above. The reduction is typically conducted byallowing the compound of Formula VI to react with a reducing agent inthe presence of a metal ion and a complexing agent for the metal ion (aligand).

The reaction temperature of this reduction reaction can vary between−20° C. and +45° C., and is preferably between +20° C. and +35° C.Advantageously, the reaction temperature is about +30° C.

Suitable solvents to be used in this reduction step include methanol,ethanol, i-propanol, dimethylformamide (DMF), and tetrahydrofuran (THF).If DMF or THF are used as solvents, water or an alcohol (such asmethanol, ethanol or i-propanol) must be present (typically in an amountof ≥1 eq). Advantageously, the solvent combination contains water andTHF. In one embodiment, the solvent combination contains an aqueous NaOHsolution, a carboxylic acid (such as acetic acid), and THF.

In one embodiment, the pH of the reaction mixture is maintained at aboutpH 9.5 to about pH 10.5.

Suitable reducing agents include sodium borohydride (NaB₄), lithiumborohydride, potassium borohydride, tetraalkylammonium borohydride andzinc borohydride. In one embodiment, the reducing agent is NaBH₄.

Preferably, the metal ion is cobalt (Co⁺² or Co⁺³). Sources of cobaltinclude cobalt dichloride (CoCl₂), cobalt diacetate (Co(OAc)₂, andCoCl₃. Preferably, the metal ion is Co²⁺.

Suitable ligands include dimethylglyoxime, 2,2′-bipyridyl, and1,10-phenanthroline, and preferably dimethylglyoxime. The ligand shouldbe used at least a 2:1 mole ratio with the cobalt ion, and preferably ata 50:1 ratio.

In another embodiment, the reduction is conducted under an inertatmosphere, such as, e.g., under a nitrogen atmosphere.

The process of the present disclosure further comprises deprotecting thecompound of Formula VII, and optionally further treating with an acid,to give a compound of Formula I:

or a pharmaceutically acceptable salt thereof. The deprotection (i.e.,the removal of the silyl ether protecting group) can be conducted in asuitable solvent by treating with acids or fluorides (e.g.,tetra-n-butylammonium fluoride) as described, e.g., in Greene, T. W. andWuts, P. G. M., Protective Groups in Organic Synthesis, p. 114 (J. Wiley& Sons, 1999). Subsequently, the deprotected compound of Formula I canbe treated with a suitable acid (such as hydrochloric acid) to form thesalt of the compound of Formula I.

In one embodiment, the deprotection of the compound of Formula VII andthe salt formation are conducted in two separate steps as describedabove.

In another embodiment, the deprotection of the compound of Formula VIIand the salt formation are simultaneous under the reaction conditions.The term “simultaneous” herein means that the deprotection and the saltformation happen at the same time or sequentially. For example, thecompound of Formula I hydrochloric acid salt can be obtainedsimultaneously by treating the compound of Formula VII with 30%hydrochloric acid in methanol at an elevated temperature from about 35°C. to about 45° C., and preferably at about 40° C.

In one embodiment, the process further comprises isolating the compoundof Formula I, or a pharmaceutically acceptable salt thereof, andoptionally purifying the isolated compound of Formula I, or apharmaceutically acceptable salt thereof.

In another embodiment, the process further comprises precipitating thecompound of Formula I, or a pharmaceutically acceptable salt thereof. Inone embodiment, the precipitating is conducted by treating the reactionmixture with a polar aprotic solvent, such as acetonitrile, at anelevated temperature, such as at reflux temperature, and then allowingthe reaction mixture to cool to room temperature, e.g., 20-25° C. Inanother embodiment, the process further comprises isolating theprecipitate comprising the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, from the reaction mixture. In one embodiment,the precipitate is isolated by filtration. In another embodiment, theisolated precipitate is further purified by, e.g., washing with thesolvent used in the precipitation and/or a mixture of the solvent andwater. In another embodiment, the isolated precipitate is washed withacetonitrile and/or a mixture of acetonitrile and water, to obtain theisolated compound of Formula I, or a pharmaceutically acceptable saltthereof.

In another embodiment, the isolated compound of Formula I, or apharmaceutically acceptable salt thereof, is further purified. In oneembodiment, the isolated compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is purified by dissolving the isolated compoundin a suitable solvent (e.g., in aqueous methanol) and treating thesolution with activated charcoal (e.g., a suspension in methanol) at anelevated temperature (e.g., at about 45° C.) for a sufficient time(e.g., 1 hour), filtering the activated charcoal, and then recoveringthe purified compound of Formula I, or a pharmaceutically acceptablesalt thereof, from the filtrate.

The compound of Formula I, and pharmaceutically acceptable saltsthereof, can be obtained in a good yield with high purity. In certainaspects of the disclosure, the inventors have obtained the compound ofFormula I using the process described above at about 13% overall yield.In certain aspects of the disclosure, the inventors have obtained thecompound of Formula I using the process described above at about 6%overall yield. As described above, the yield of the compound for FormulaI depends on the yield and purity of the intermediate of Formula III.

In another embodiment, the process further comprises deuterating thecompound of Formula I, or a pharmaceutically acceptable salt thereof. Inanother embodiment, the isolated compound of Formula I, or apharmaceutically acceptable salt thereof, is deuterated. Methods knownin the art can be used for preparing the deuterated compounds of FormulaI, and the pharmaceutically acceptable salts thereof. For example, suchmethods are described in WO 2014/152843 A1.

In one embodiment of the present disclosure, the compound of Formula IIis prepared by protecting the hydroxyl group of a compound of FormulaVIII:

wherein LG¹ is a leaving group, as defined above, with PG, wherein PG isa protecting group, e.g., a protecting group selected from the groupconsisting of silyl protecting groups, tetrahydropyranyl, methoxymethyl,and benzyl. The protection of the hydroxyl group by a silyl protectinggroup, tetrahydropyranyl, methoxymethyl, or benzyl can be performed bymethods known in the art. For example, if PG is a silyl protectinggroup, the compound of Formula VIII can be reacted with a silyl chloride(such as TBDMS-Cl, TMS-Cl, TBDPS-Cl, and TIPS-Cl) using an amine base(such as imidazole). One possible procedure is the Corey protocol inwhich the compound of Formula VIII is reacted with a silyl chloride andimidazole at high concentration in DMF.

In one embodiment of the present disclosure, the compound of FormulaVIII is prepared by reacting a compound of Formula IX:

wherein LG¹ is a leaving group, as defined above, with CH₃CHO in thepresence of an alkylmagnesiumhalide in the presence of a solvent to givethe compound of Formula VIII. Suitable alkylmagnesiumhalides include,for example, i-PrMgCl, t-BuMgCl, and t-BuMgBr. Compounds of Formula IXwhere LG¹ is a halogenide are also commercially available from, forexample, OxChem Corporation. Suitable solvents include anhydrousethereal solvents, such as THF and diethyl ether, and preferably THF.

The term “pharmaceutically acceptable salt” refers to a salt preparedfrom pharmaceutically acceptable inorganic and organic acids. Exemplarypharmaceutically acceptable acid addition salts of the Compounds of theDisclosure include, without limitation, hydrochloric, hydrobromic,hydroiodic, sulfuric, phosphoric, formic, acetic, trifluoroacetic,propionic, citric, and benzoic acids.

The term “hydroxyl protecting group” or a “protecting group” as usedherein refers to group that blocks (i.e., protects) the hydroxyfunctionality while reactions are carried out on other functional groupsor parts of the molecule. Those skilled in the art will be familiar withthe selection, attachment, and cleavage of protecting groups and willappreciate that many different protective groups are known in the art,the suitability of one protective group or another being dependent onthe particular synthetic scheme planned. Suitable hydroxyl protectinggroups are generally able to be selectively introduced and removed usingmild reaction conditions that do not interfere with other portions ofthe subject compounds. These protecting groups can be introduced orremoved at a convenient stage using methods known in the art. Thechemical properties of such groups, methods for their introduction andremoval are known in the art and can be found, for example, in Wuts, P.G. M. & Greene, T. W., Greene's Protective Groups in Organic Synthesis,4rd Ed., pp. 16-430 (J. Wiley & Sons, 2007), herein incorporated byreference in its entirety. Unless specifically specified, suitablehydroxyl protecting groups are disclosed in Wuts, P. G. M. & Greene, T.W., above. Additional hydroxyl protecting groups can be found, forexample, in U.S. Pat. No. 5,952,495, U.S. Patent Appl. Pub. No.2008/0312411, WO 2006/035195, and WO 98/02033, herein incorporated intheir entirety. Suitable hydroxyl protecting groups include themethoxymethyl, tetrahydropyranyl, tert-butyl, allyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl,benzoyl, benzyl (Bn), and p-methoxybenzyl group.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

Some of the compounds disclosed herein may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms, such as epimers. The present inventionis meant to encompass the uses of all such possible forms, as well astheir racemic and resolved forms and mixtures thereof. The individualenantiomers may be separated according to methods known to those ofordinary skill in the art in view of the present disclosure. When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that they include both E and Z geometric isomers. All tautomersare intended to be encompassed by the present invention as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “epimer” refers to diastereomers that have oppositeconfiguration at only one of two or more tetrahedral stereogenic centerspresent in the respective molecular entities.

The term “stereogenic center” is an atom, bearing groups such that aninterchanging of any two groups leads to a stereoisomer.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

Open terms such as “include,” “including,” “contain,” “containing” andthe like mean “comprising.”

The term “alkali metal” as used herein refers to sodium (Na), potassium(K), and lithium (Li). In one embodiment, the term “alkali metal” canalso refer to cesium (Cs).

The term “carbonate” as used herein refers to a salt of carbonic acidcharacterized by the presence of the carbonate ion CO₃ ²⁻.

The term “alkali metal carbonate” as used herein refers to a carbonatesalt of any of the above mentioned alkali metals. Alkali metalcarbonates include K₂CO₃, Na₂CO₃, Li₂CO₃, KHCO₃, and NaHCO₃.

The term “alkyl” as used herein by itself or as a part of another grouprefers to unsubstituted straight-chain, branched or cyclic aliphatichydrocarbon containing from one to twelve carbon atoms, i.e., C₁₋₁₂alkyl. In one embodiment, the alkyl group is C₁₋₆ alkyl. Exemplary C₁₋₆alkyl groups include methyl, ethyl, propyl, iso-propyl, n-butyl,tert-butyl, sec-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “lower alkyl” refers to C₁₋₄ alkyl that is a straight-chain orbranched-chain aliphatic hydrocarbon. Lower alkyl groups include methyl,ethyl, propyl, iso-propyl, n-butyl, sec-butyl, and tert-butyl.

The term “organosulfonate” as used herein refers to an organic anionR—SO₃ ⁻, wherein R can be an organic group, such as methyl, ethyl,benzene, and p-toluene.

The term “silyl protecting groups” as used herein refers to a group ofchemical compounds which contain silicon atom that can be covalentlybonded to an alkoxy group. Thus, a silyl ether is formed.

The term “alkoxy” as used herein refers to a radical of the formula—O—R², where R² is a group having an alkyl group attached to the oxygenatom.

The terms “deuteration” or “deuterating” and the like as used hereinrefers to incorporating deuterium at one or more positions of Formula Iin place of hydrogen at that position(s). In one embodiment, thedeuterium enrichment is about 15% or more, i.e., at least about 1000times greater than the natural abundance of deuterium. In anotherembodiment, the deuterium enrichment is about 20% or more, about 25% ormore, about 30% or more, about 35% or more, about 40% or more, about 45%or more, about 50% or more, about 55% or more, about 60% or more, about65% or more, about 70% or more, about 75% or more, about 80% or more,about 85% or more, about 90% or more, about 95% or more, about 98% ormore, or about 99% or more. In another embodiment, the deuteriumenrichment is about 100%. The deuterium enrichment can be determinedusing conventional analytical methods known to one of ordinary skill inthe art, including mass spectrometry and nuclear magnetic resonancespectroscopy.

When a position of Formulae I is designated specifically as “H” or“hydrogen,” the position is understood to have hydrogen at its naturalabundance isotopic composition.

When a position of Formulae I is designated specifically as “D” or“deuterium,” the position is understood to have deuterium at anabundance that is at least about 1000 times greater than the naturalabundance of deuterium, which is about 0.015%.

In one embodiment, a deuterated compound of Formula I has the followingstructure:

See, the preparation in Example 8.

In another embodiment, deuterium is incorporated at more than oneavailable position of Formula I, e.g., 1, 2, 3, 4, 5, or 6 availablepositions. In another embodiment, deuterium is incorporated at allavailable positions of Formula I. Deuterated starting compounds can usedto prepare a deuterated compound of Formula I, or a pharmaceuticallyacceptable salt thereof. Such starting compounds can be, for example,deuterated acetaldehyde, deuterated ethylene oxide, or deuterated4-hydroxybenzaldehyde.

In one embodiment, the disclosure provides a process for preparing thecompound of Formula I illustrated by Scheme 2:

In another embodiment, the disclosure provides a process for preparingthe compound of Formula I illustrated by Scheme 3:

In another embodiment in Scheme 3, step c, the order of mixing of thereagents can be as follows: 1. n-BuLi, 2. ethylene oxide, and 3. CuI.This order of mixing is described in Example 2.

In the step a, 2,5-dibromopyridine (1) is reacted with i-PrMgCl in THFand then further with acetaldehyde to obtain compound 2. The reactionmixture is preferably filtered over Celite® after the reaction to removemost of the salts. In one embodiment, the addition of acetaldehyde isconducted at a temperature between −15° C. and −10° C. to control theexothermic reaction.

In the step b, compound 2 is reacted with TBDMS-Cl in the presence ofimidazole having DMF as a solvent. The crude product 3 is advantageouslypurified by a short plug filtration.

In the step c, the hydroxyl protected compound 3 is reacted withethylene oxide in the presence of n-BuLi and Cu(I)iodide whilemaintaining the reaction temperature, i.e., the reaction mixturetemperature, below −20° C. In one embodiment, the reaction temperatureis maintained below −55° C. while adding n-BuLi and Cu(I)iodide into thereaction mixture. In another embodiment, the temperature of the reactionmixture is maintained below −55° C. while adding n-BuLi, followed byethylene oxide and then Cu(I)iodide into the reaction mixture. Inanother embodiment, the temperature of the reaction mixture ismaintained below −55° C. while adding n-BuLi into the reaction mixture,followed by ethylene oxide. In this embodiment, Cu(I)iodide is addedthen into the reaction mixture while the reaction mixture temperature ismaintained below −20° C., and preferably below −55° C. The reactionmixture is then allowed to slowly warm to room temperature after theaddition of the reagents and stirred at room temperature, e.g., 20-25°C., overnight. This process is described in detail in Example 2. Afterthe reaction, the complexed copper is advantageously removed by washingwith 10% ammonia. The crude compound 4 can be purified by columnchromatography to give >99% pure product with a yield of about 52%.

The following examples are illustrative, but not limiting, of themethods of the present invention. Suitable modifications and adaptationsof the variety of conditions and parameters normally encountered inclinical therapy and which are obvious to those skilled in the art inview of this disclosure are within the spirit and scope of theinvention.

EXAMPLES Comparative Example 1 Synthesis of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(9a) According to the Process Described in WO 2015/150476 A1

(a) Synthesis of 1-(6-methyl-pyridin-3-yl)-ethanol (3a)

LiHMDS (1.0 M in tetrahydrofuran, 463 ml, 0.463 mol) was added drop wiseto a cooled solution of methyl 6-methylnicotinate (1a) (20 g, 0.132 mol)and ethyl acetate (82 g, 0.927 mol) in dimethylformamide at −50° C.;gradually raised the temperature to room temperature and stirred at thesame temperature. After 1 h, the reaction mixture was cooled to 0°C.:slowly diluted with 20% sulphuric acid and heated to reflux. After 4h, the reaction mixture was cooled to room temperature. and further to0° C. and basified with potassium carbonate. The reaction medium wasdiluted with water and extracted in ethyl acetate (3×50 mL). Combinedorganic extract was dried over sodium sulphate and concentrated toafford crude 1-(6-methylpyridin-3-yl)ethan-1-one (2a) (20.0 g) which wastaken to the next step without any purification. ES-MS [M+1]+: 136.1.

Sodium borohydride (2.3 g, 0.06 mol) was added in small portions over 30min, to a solution of compound 2a (16.4 g, 0.121 mol) in ethanol (160mL) at 0° C. and the reaction mixture was stirred at same temperature.After 1 h, the reaction mixture was diluted with sodium bicarbonatesolution (sat) (2×200 mL) and extracted with dichloromethane (2×500 mL).The combined organic extract was dried over anhydrous sodium sulphateand concentrated to afford a pale yellow oil, which was purified byflash column chromatography (5% methanol/dichloromethane) to affordcompound 3a (17.0 g; 93% yield over 2 steps) as a pale yellow oil. ES-MS[M+1]⁺: 138.1. ¹H NMR (400 MHz, CDCl₃): δ 8.35 (d, J=2.0 Hz, 1H), 7.63(dd, J=8.0, 2.4 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.89 (q, J=6.5 Hz, 1H),3.30 (br s, 1H), 2.50 (s, 3H), 1.48 (d, J=6.5 Hz, 3H).

(b) Synthesis of 5-(I-methoxymethoxy-ethyl)-2-methyl-pyridine (4a)

Compound 3a (15 g, 0.109 mol) was added, drop wise, to a cooledsuspension of sodium hydride (6.56 g, 0.164 mol) in tetrahydrofurane(150 mL) and stirred at 0° C. After 30 min, chloromethyl methyl ether(13.2 g, 0.164 mol) was added drop wise while stirring and keeping theinternal temperature around 0° C. After addition is over, the reactionmixture was stirred at the same temperature for 1 h. The reaction wasquenched with ice cold water (80 mL) and extracted with ethyl acetate(3×50 mL). The combined organic extract was dried over anhydrous sodiumsulphate and concentrated to afford an orange color oil, which waspurified by flash column chromatography (1% methanol/dichloromethane) toafford compound 4a (10.0 g: 51% yield) as a pale yellow oil. ES-MS[M+1]⁺: 182.2. ¹H NMR (400 MHz, CDCl₃): δ 8.45 (d, J=2.0 Hz, 1H), 7.56(dd, J=8.0, 2.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.75 (q, J=6.4 Hz, 1H),4.57 (ABq, 2H), 3.36 (s, 3H), 2.53 (s, 3H), 1.48 (d, J=6.6 Hz, 3H).

(c) Synthesis of 2-[5-(1-methoxymethoxy-ethyl)-pyridin-2-yl]-ethanol(5a)

A mixture of compound 4a (7.0 g, 0.0386 mol) and 37% formaldehydesolution (5.8 g, 0.077 mol) was heated to 160° C. in a sealed glass tubefor 5 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure to afford a crude compound which waspurified by flash column chromatography (1% methanol/dichloromethane) toafford compound 5 (1.2 g; 17% yield) as pale yellow oil. ES-MS [M+1]⁺:212.1. ¹H NMR (400 MHz, CDCl₃): δ 8.42 (d, J=2.0 Hz, 1H), 7.65 (dd,J=8.0, 2.4 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.72 (q, J=6.6 Hz, 1H), 4.65(t, J=5.6 Hz, 1H), 4.52 (ABq, 2H), 3.73 (m, 2H), 3.24 (s, 3H), 2.86 (t,J=7.2 Hz, 2H), 1.49 (d, J=6.4 Hz, 3H).

The total yield for compound 5a from compound 1a was 8% molar.

(d) Synthesis of4-{2-[5-(1-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}-benzaldehyde (6a)

Methanesulphonylchloride (1.19 g, 0.01 mol) was added, drop wise, to acooled suspension of compound 5a (1.7 g, 0.008 mol) and triethylamine(1.79 ml, 0.013 mol) in dichloromethane (20 mL) at 0° C. and stirred atsame temperature for 1 h. The reaction mixture was diluted with water(50 mL) and extracted with dichloromethane (3×50 mL). The combinedorganic extract was dried over anhydrous sodium sulphate andconcentrated to afford 2-(5-(1-(methoxymethoxy)ethyl)pyridin-2-yl)ethylmethanesulfonate (2.04 g; 88% yield) as a yellow oil, which was taken tonext step without purification. ES-MS [M+1]⁺: 290.

2-(5-(1-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate wasadded (2.3 g, 0.008 mol) to a stirred suspension of4-hydroxybenzaldehyde (1.65 g, 0.0137 mol) and potassium carbonate (1.86g, 0.0137 mol) in mixture of toluene (25 mL) and ethanol (25 mL);stirred at 85° C. for 5 h. After consumption of the starting materials,the reaction mixture was diluted with water (30 mL) and extracted withethyl acetate (2×100 mL). The combined organic extract was washed withwater; dried over anhydrous sodium sulphate and concentrated to afford acrude dark yellow liquid. The crude was purified by flash columnchromatography (1% methanol/dichloromethane) to afford compound 6a (1.5g; 60% yield) as pale yellow liquid. ES-MS [M+1]⁺: 316.1.

(e) Synthesis of5-(4-{2-[5-(1-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione(7a)

Piperidine (80 mg, 0.95 mmol) was added to a solution of compound 6a(0.6 g, 1.9 mmol) and thiazolidine-2,4-dione (0.22 g, 1.9 mmol) inethanol (15 mL) and the mixture was heated to reflux overnight. After 15h, the reaction mixture was cooled to room temperature and concentratedunder reduced pressure to afford crude mixture, which was purified byflash column chromatography (2% methanol/dichloromethane) to affordcompound 7 (500 mg; 64% yield) as a yellow solid. ES-MS [M+1]+: 415.1.¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (br s, 1H), 8.47 (d, J=2.0 Hz, 1H),7.70 (dd, J=8.0, 2.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.0 Hz,1H), 7.21 (d, J=8.8 Hz, 2H), 4.73 (m, 1H), 4.60-4.40 (m, 4H), 4.22 (t,J=6.2 Hz, 1H), 3.24 (s, 3H), 3.20 (t, J=6.8 Hz, 2H), 1.41 (d, J=6.0 Hz,3H).

(f) Synthesis of5-(4-{2-[5-(1-hydroxy-ethyl)-pyridin-2-yl]-ethoxy}-benzyl)-thiazolidine-2,4-dione(9a)

A solution of sodium borohydride (115 mg, 3.017 mmol) in 0.2N sodiumhydroxide (1.2 mL) was added slowly to a stirred solution of compound 7(0.5 g, 1.207 mmol), dimethylglyoxime (42 mg, 0.36 mmol) and CoCl₂.6H₂O(23 mg, 0.096 mmol) in a mixture of water (6 mL):tetrahydrofurane (6 mL)and 1M sodium hydroxide (1 mL) solution at 10° C. and after addition,the reaction mixture was stirred at room temperature. After 1 h, thereaction color lightened and additional quantities of sodium borohydride(46 mg, 1.207 mmol) and CoCl₂.6H₂O (22 mg, 0.096 mmol) were added andstirring was continued at room temperature. After 12 h, the reaction wasneutralized with acetic acid (pH-7); diluted with water (10 mL) andextracted in ethyl acetate (3×50 mL). The combined organic extract wasdried over anhydrous sodium sulphate and concentrated to afford crudecompound 8a,5-(4-(2-(5-(1-(methoxymethoxy)ethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione,(0.4 g) as pale yellow semi solid, which was taken to next step withoutpurification. ES-MS [M+1]⁺: 417.5.

2N HCl (2 mL) was added to a solution of compound 8a (0.4 g, 0.96 mmol)in methanol (20 ml) and the mixture was heated to reflux. After 4 h, thereaction mixture was cooled to room temperature and then concentratedunder reduced pressure to afford a residue which was dissolved in waterand the solution was neutralized using sodium bicarbonate solution(sat). The resulting white precipitate was collected by filtration toafford compound 9a (250 mg; 56% yield over 2 steps) as an off-whitesolid. ES-MS [M+1]+: 373.4. ¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (br s,—NH), 8.46 (d, J=2.0 Hz, 1H), 7.66 (dd, J=8.0, 2.4 Hz, 1H), 7.30 (d,J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.25 (d,J=4.4 Hz, 1H), 4.86 (m, 1H), 4.75 (m, 1H), 4.30 (t, J=6.8 Hz, 2H), 3.30(m, 1H), 3.14 (t, J=6.4 Hz, 2H), 3.04 (m, 1H), 1.34 (d, J=6.4 Hz, 3H).

The overall yield of compound 9a was 1.5% molar.

Example 2 Synthesis of2-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-1-ol

The synthesis of2-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-1-ol wasconducted according to the Scheme 5 using the reagents and solventslisted in Table 1 below:

The 1H-NMR spectra were recorded with Agilent MercuryPlus 300 NMRspectrometer.

LC-MS data were obtained on an Agilent 1290 series with UV detector andHP 6130 MSD mass detector using as column Waters XBridge BEH XP (2.1×50mm; 2.5 μm) and as eluent Ammonium acetate (10 mM);Water/Methanol/Acetonitrile.

(a) 1-(6-bromopyridin-3-yl)ethan-1-ol (2)

A 20 L vessel was placed under nitrogen atmosphere and charged withtetrahydrofuran (5.5 L) and 2,5-dibromopyridine (1) (2000 g, 8.44 mol,1.0 eq) (OxChem Corporation). The mixture was cooled to −10° C. andisopropyl magnesium chloride (20% in THF, 6.02 L, 11.82 mol, 1.4 eq)(Rockwood Lithium) was added slowly over 1 h, keeping the reactiontemperature below 5° C. After addition, the cooling bath was removed andthe temperature was kept below 30° C. (some additional cooling wasneeded to achieve this) and the reaction mixture was stirred overnight.After 16 h, a sample was taken; quenched with saturated aqueous ammoniumchloride and extracted with methyl tert-butyl ether (TBME). The TBME wasevaporated under vacuum. ¹H-NMR in deuterated chloroform showed completeconversion.

The reaction mixture was cooled to −15° C. and a solution ofacetaldehyde (472 g, 10.72 mol, 1.27 eq) (Acros) in tetrahydrofuran (200mL) was added dropwise, while keeping temperature below −10° C. Afterthe addition was complete, the cooling bath was removed and thetemperature was allowed to rise to maximum of 5-8° C. After 1.5 h, asample was taken and the reaction was quenched with aqueous ammoniumchloride as described above, ¹H-NMR showed the reaction was complete.

Two batches were combined for work up.

The reaction mixture was quenched by pouring the mixture into a solutionof aqueous ammonium chloride (I kg in 5 L water) and stirred for 15 min,filtered over Celite® and rinsed thoroughly with toluene. The filtratewas transferred to a separation funnel and the obtained two layerssystem was separated. The aqueous layer was extracted with toluene (2L). The combined organic layers were dried over sodium sulfate andfiltered. Evaporation of the filtrate to dryness under vacuum yielded3.49 kg (99%) of the desired crude material. ¹H NMR (300 MHz, CDCl₃): δ8.30 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.0, 2.5 Hz, 1H), 7.44 (d, J=8.0 Hz,1H), 4.91 (q, J=6.5 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).

(b) 2-bromo-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridine (3)

A 50 L reactor under nitrogen atmosphere was charged with compound 2(10.0 kg, around 49.5 mol) and DMF (16 L). The mixture was cooled to 10°C. and imidazole (6.74 kg, 99 mol, 2.0 eq) (Apollo Scientific Ltd.) wasadded portion wise within 30 min. The mixture was cooled to 0° C. andTBDMS-Cl (7.46 kg, 49.5 mol, 1.0 eq) (Fluorochem) was added portion wisewithin 5 h, keeping the temperature below 3° C. The mixture reactiontemperature was allowed to reach room temperature and stirred overnight.¹H NMR of a sample showed complete conversion.

The reaction mixture was transferred to a 100 L extraction-vessel andthe product was extracted with heptane (2×7.5 L, 10 L). The combinedheptane-layers were washed with water (2×6 L, 3 L) to remove smallamounts of DMF, dried over sodium sulfate and evaporated under vacuum togive crude compound 3 (15.5 kg, 49.0 mol) in a 99.0% yield. This crudeproduct was purified by a short plug filtration, using 10 kgsilica/heptane and eluted with heptane (approx. 50 L). Theproduct-fractions were combined and evaporated under vacuum to give 12.0kg of purified compound 3 (38 mol) as a brown oil in a 76.8% molaryield. (Average yield for 3 experiments was 78%). HPLC-MS: Rt=2.6 min,M+1=316.1 and 318.1; ¹H NMR (300 MHz, CDCl₃): δ 8.55 (d, J=2.2 Hz, 1H),7.54 (dd, J=8.2, 2.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 4.86 (q, J=6.5 Hz,1H), 1.40 (d, J=6.5 Hz, 3H), 0.88 (s, 9H), 0.02 (d, J=26 Hz, 2×3H).

(c) 2-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-1-ol(4)

The ethylene oxide solution in diethylether was prepared in advance.Diethylether (1.2 L) in a 3 L three-necked flask was cooled at −65° C.and ethylene oxide (462.3 g, 10.5 mol, 1.06 eq) (Linde) was added andstirred at −70° C. Alternatively, the ethylene oxide solution can bemade at about −20° C. and then added gradually to the reaction mixturehaving a temperature at about −60° C.

To a solution of2-bromo-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridine (3) (3.13 kg,9.90 mol, 1.0 eq) in diethylether (7.5 L) cooled at −59° C.,n-butyllithium (4 L, 10.0 mol, 2.5M in hexanes, 1.01 eq) (AldrichChemistry) was added while keeping temperature between −58° C. and −62°C. After addition, the mixture was stirred for 1 h while keepingtemperature between −60° C. and −68° C. The upfront prepared ethyleneoxide solution was added at once to the reaction mixture, whiletemperature was around −62° C. Subsequently, copper(I) iodide (962.3 g,5.05 mol, 0.51 eq) (Acros Organics) was added in portions of 120 g,every 10 min, keeping the temperature between −61° C. and −63° C.Stirring was continued for 1 h after addition keeping temperaturebetween −61° C. and −63° C. The cooling bath was removed and allowingthe temperature to rise to about 15° C. and further to 25° C. with awater bath overnight.

Workup: The reaction-mixture was poured into a solution of 1 kgammonium-chloride in 5 L water and stirred for 30 min, then the layerswere separated. The organic layer was washed with aqueous ammoniumhydroxide (10%, 2.5 L, 4×) to remove Cu-complex (blue colordisappeared). The combined organic layers were dried over sodium sulfateand evaporated to give 3.12 kg (max. 9.90 mol) crude compound 4 as abrown oil. The crude compound was purified over 20 kg silica(heptane/EtOAc) by eluting with 80 L heptane/EtOAc, 20 L EtOAc, 25 LEtOAc/MeOH 95/5, 25 L EtOAc/MeOH 9/1 and 10 L EtOAc/MeOH 8/2, to give1.47 kg of purified compound 4 (5.22 mol) as a brown oil (with tendencyto solidify) in a 52.7% average molar yield (HPLC-purity of 99.5%).(Average yield over 12 experiments 52%). HPLC-MS: Rt=2.3 min, M+1=282.1;¹H NMR (300 MHz, CDCl₃): δ 8.42 (d, J=2.1 Hz, 1H), 7.61 (dd, J=8.3, 2.1Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 4.88 (q, J=7.0 Hz, 1H), 4.01 (t, J=6.0Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 1.41 (d, J=7.0 Hz, 3H), 0.90 (s, 9H),0.02 (d, J=26 Hz, 2×3H).

Another 2.5% of the product was isolated by re-purifying impure productfraction. The total yield of compound 4 from compound 1 was 39.6% molar.

Example 3 Synthesis of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionehydrochloride (9)

The ¹H-NMR spectra were recorded with a 400 MHz Avance Bruker NMRspectrometer. LC-MS data were obtained on a Agilent Technologies 6130Quadrapole LC/MS using as column Agilent XDB-C18 and as eluent 0.1%formic acid (aq) and 0.05% formic acid in acetonitrile.

Steps d and e: Synthesis of4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]-benzaldehyde(6)

To a well stirred solution of5-[[[(1,1-dimethylethyl)dimethylsilyl]-oxy]ethyl]-2-pyridineethanol (4)(obtained as described in Example 2) (1.91 kg) in toluene (8.6 L) at 5°C. were added sodium hydroxide (30% aqueous, 2.79 L) andtetrabutylammonium bromide (7.2 g). p-Toluenesulfonyl chloride (1.62 kg)was next added in portions during 5 min. After the addition, thereaction mixture was allowed to reach room temperature in 0.5 h andstirred at this temperature for 18 h. Water (7.3 L) was then added andthe mixture was mixed well. Once the solids were dissolved, the layerswere allowed to settle and the organic layer was separated. This organicphase was washed with water (5.7 L, 2×), followed by washing with asolution of sodium chloride (57 g) in water (5.7 L). The solvents wereconcentrated at reduced pressure to an amount of 2.5 kg of a brown oil(compound 5).

To this well stirred brown oil were added subsequently ethanol (7.8 L),water (0.86 L), 4-hydroxybenzaldehyde (0.88 kg) and potassium carbonate(1.17 kg) and then the mixture was heated at 75° C. for 18 h. Then, thesolvent was evaporated while adding toluene (7.7 L) during 6 h and thenthe reaction mixture was allowed to cool. At 30° C., water (7.6 L) wasadded, stirred until all solids were dissolved and the mixture wascooled to room temperature. The layers were allowed to settle andseparated. The organic layer was washed with water (7.6 L). The firstaqueous extract was extracted with toluene (2.8 L) and this organicextract was used to also extract the aqueous washing. The organicextracts were combined and concentrated under vacuum to give 3.49 kg ofa black oil (crude title compound 6).

1.73 kg of this black oil was dissolved in ethanol (0.74 L) and added toa well stirred solution of sodium bisulfite (1.36 kg) in a mixture ofwater (3.27 L) and ethanol (0.74 L). The container of the black oil wasrinsed with ethanol (0.37 L) twice and these two rinses were also addedto the bisulfite reaction mixture. After 75 min, heptane (5.3 L) wasadded, well mixed for 5 min, and the layers were allowed to settle andseparated. To the organic layer was added a solution of sodium bisulfite(0.55 kg) in water (2.65 L), and ethanol (1.06 L). After stirring for 30min, the layers were allowed to settle and separated. The two bisulfideaqueous extracts were combined and flasks rinsed with water (2.12 L).Next, toluene (4.5 L) and heptane (4.5 L) were added, the mixture waswell stirred and the pH was adjusted to 12 using sodium hydroxide (10%aq) (temperature became 32° C.). After stirring for an additional 5 min,the layers were allowed to settle and separated at 30° C. The aqueouslayer was extracted with a mixture of toluene (1.5 L) and heptane (3.0L). The layers were separated and the organic layers were combined. Thecombined organic layers were washed with water (5 L, 2×) andconcentrated under vacuum to give the purified title compound 6. Thisprocedure was repeated with another 1.73 kg of the black oil (crudetitle compound 6) to give in total 2.77 kg of4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]-benzaldehyde(6) as brown oil which contained 24% m/m of toluene according to ¹H NMR(yield=80%, calculated from compound 4 and corrected for residualtoluene).

¹H NMR (CDCl₃) δ: 0.00 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.44 (d, J=6Hz, 3H), 3.30 (t, J=7 Hz, 2H), 4.47 (t, J=7 Hz, 2H), 4.92 (q, J=6 Hz,1H), 6.99-7.30 (m, 3H), 7.62-7.67 (m, 1H), 7.80-7.85 (m, 2H), 8.5-8.54(m, 1H) and 9.88 (s, 1H).

LC-MS; rt 7.5 min: ES: M⁺ 387, 386.

Step f: Synthesis of(5Z)-5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione(7)

A solution of4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]-ethoxy]-benzaldehyde(6) (2.75 kg, containing 24% m/m of toluene) and piperidine (6.0 g) inmethanol (3.16 L) was concentrated at 40° C. under reduced pressure. Theresidue was dissolved in methanol (10.4 L) and 2,4-thiazolidinedione(759 g) and piperidine (230 g) were added. The mixture was heated at 47°C. After 25 h, the reaction mixture was allowed to cool to roomtemperature. The mixture was kept at pH 5-6 by adjusting it with aceticacid, if necessary. After a night at room temperature, water (1.56 L)was added and the suspension was stirred at room temperature foradditional 2 h. The solids were isolated by filtration, washed withmethanol (1 L, 2×) and dried under vacuum to give crude compound 7 (1.65kg). The crude compound was mixed with methanol (10 L) anddichloromethane (8.6 L) and heated at 32° C. until all solids dissolved.Then, the solvents were removed by distillation until the temperature ofthe mixture reached 34° C. at a pressure of 333 mbar. Then, it wasallowed to cool to room temperature overnight and stirred at 2° C. foradditional 2 h. The solids were isolated by filtration, washed withmethanol (0.5 L, 2×) and dried under vacuum to give title compound 7(1.50 kg) (yield=61%).

¹H NMR (CDCl₃) δ 0.00 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.43 (d, J=6Hz, 3H), 3.32 (t, J=7 Hz, 2H), 4.48 (t, J=7 Hz, 2H), 4.92 (q, J=6 Hz,1H), 6.95-7.00 (m, 2H), 7.24-7.28 (m, 1H), 7.38-7.42 (m, 2H), 7.67 (s,1H), 7.69-7.73 (m, 1H) and 8.48 (d, J=3 Hz, 1H).

LC-MS; rt 7.5 min: ES: M⁺ 487, 486, 485.

Step g: Synthesis of5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(8)

To a stirred suspension of(5Z)-5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]-ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione(7) (10 g) in THF (10 mL) and sodium hydroxide (1N aq, 21 mL) was addedof a solution of cobalt chloride (26 mg) and of dimethylglyoxime (930mg) in THF (2.3 mL) and water (1.0 mL). Then the suspension was putunder a nitrogen atmosphere by applying the sequence of vacuum andflushing with nitrogen (4×). Thereafter, the suspension was heated to30° C. Then, a stock solution of sodium borohydride was prepared bydissolving sodium borohydride (2.7 g) in a mixture of water (15.8 mL)and a solution of sodium hydroxide (1 N aq, 3.5 mL), which was put undera nitrogen atmosphere by applying a sequence of vacuum and flushing withnitrogen (3×). This was added to the suspension of compound 7 at a rateof 4.5 mL/h. Simultaneously, nitrogen gas-saturated acetic acid wasadded to the suspension at a rate of 0.7 mL/h to maintain a pH of10.0-10.5. After 1 h 30 min the rate of addition of the sodiumborohydride solution and acetic acid were both reduced by half. Next, 3h 45 min after start of addition, the addition of sodium borohydride andacetic acid were stopped. The mixture was allowed to cool down to roomtemperature and acetone (2.5 mL) was added over a period of 1 minute.After stirring the reaction mixture for 15 min acetic acid was addeduntil the pH was 5.5-6.0 (about 3 mL required). Next, a mixture of ethylacetate/toluene (1/3 v/v, 30 mL) was added, well mixed and layers wereallowed to settle. The aqueous layer was separated and washed with ethylacetate/toluene (1/3 v/v, 10 mL). Both organic extracts were pooled andwater (40 mL) was added, well mixed and layers were allowed to settle.The pH of the aqueous layer was adjusted to 5.5-6 using saturated sodiumhydrogen carbonate solution (aq) and again mixed with the organic layer.Layers were allowed to settle and the organic layer was separated andconcentrated under vacuum to give 11.09 g of yellow oil (crude mixturecontaining title compound 8 and its borane complex). Several batcheswere combined for work up.

33.1 g of the crude mixture containing title compound 8 and its boranecomplex (not corrected for residual solvents) was dissolved in toluene(30 mL) and filtered. The filtrate was submitted to columnchromatography (silica gel, gradient of toluene to toluene/ethyl acetate1/1) to give 30.0 g of mixture of5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(8) and its borane complex as a slightly yellow oil (yield=100% fromcompound 4, not corrected for residual solvents).

¹H NMR (CDCl₃) δ: −0.03-0.10 (m, 6H), 0.87-0.93 (m, 9H), 1.42 (d, J=6Hz, 3H), 3.05-3.71 (m, 4H), 4.30-4.51 (m, 3H), 4.87-4.94 (m, 1H),6.82-6.88 (m, 2H), 7.10-7.92 (m, 5H), 8.49 (d, J=3 Hz, 0.6H) and 8.72(brs, 0.4H).

LC-MS; rt 6.8 min: ES: M⁺ 489, 488, 487, M⁻ 487, 486, 485; rt 8.1 min:ES M⁻ 501, 500, 499, 498, 485.

Step h: Synthesis of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedionehydrochloride (9)

To a stirred solution of the mixture of(5-[[4-[2-[5-[[[(1,1-dimethylethyl)-dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedioneand its borane complex (8) (5.17 g) in methanol (25.2 mL) at 22° C. wasadded hydrochloric acid (30%, 2.75 mL) in about 5 min to give atemperature rise to 28° C. This solution was heated to 40° C. Threehours after addition, the 11 g of volatiles were removed under reducedpressure. Then, acetonitrile (40.3 mL) was added and the mixture washeated at reflux for 0.5 h. Next, the suspension was allowed to cooldown to room temperature and stirred for 1 h at room temperature. Solidswere isolated by filtration, washed with a mixture of acetonitrile/water(20/1 v/v, 10 mL) and with acetonitrile (10 mL) and dried under vacuumat 40° C. to give 4.00 g of white solids (crude 9) (yield=77%, notcorrected for residual solvents).

Purification of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionehydrochloride (9)

The crude mixture of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedionehydrochloride (3.95 g, crude 9) was dissolved in methanol/water (7/2v/v, 80 mL) by heating it to 49° C. To this solution was added washednorit (obtained by heating a suspension of norit (6 g) in methanol/water(7/2 v/v, 90 mL) at 45° C. for 1 h, then isolating the norit byfiltration and washing it twice with methanol/water (7/2 v/v, 30 mL) anddrying it under vacuum at 40° C.). Equipment was rinsed withmethanol/water (7/2 v/v, 18 mL). After 0.5 h of stirring at 46° C., thewarm suspension was filtered to remove the norit and filter was washedtwice with methanol/water (7/2 v/v, 18 mL). The filtrate wasconcentrated under vacuum at a bath temperature of 60° C. to a mass of11.8 g (1 v of compound and 2 v of water). To the suspension was addedbutanone (19.7 mL, 5 v) and the mixture was heated at a bath temperatureof 95° C. Under distillation at a constant volume, butanone (95 mL) wasadded. Next, heating was stopped and the suspension was allowed to reachroom temperature in about 0.5 h. Subsequently it was stirred for 0.75 hat room temperature. The solids were isolated by filtration, washed witha mixture of butanone/water (95/5 v/v, 18 mL) and butanone (18 mL) anddried under vacuum at 40° C. to give 3.57 g of compound 9 as whitesolids (yield=91%).

¹H NMR (DMSO-d₆): δ 12.00 (br s, —NH), 8.71 (d, J=2.0 Hz, 1H), 8.45 (dd,J=8.3, 1.7 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H), 6.88(d, J=8.7 Hz, 2H), 5.57 (s, OH), 4.95 (q, J=6.5 Hz, 1H), 4.86 (dd,J=8.9, 4.4 Hz, 1H), 4.40 (t, J=6.3 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.29(dd, J=14.2, 4.4 Hz, 1H), 3.06 (dd, J=14.2, 9.0 Hz, 1H), 1.41 (d, J=6.5Hz, 3H).

LC-MS; rt 3.5 min: ES: M⁺ 374, 373, M⁻ 372, 371.

Example 4 Conditions Tested in the Preparation of Compound 5 in the Stepd

The conditions described in Table 2 below were tested in the step d inthe preparation of compound 5 from compound 4 providing a good yield ofcompound 5:

TABLE 2 Entry Reaction Conditions Amount of p-Ts-Cl/Eq 1Toluene/water/Bu₄NBr/NaOH 1.05 2 1.08 3 1.07 4 1.07 + 0.03 5 1.07 6Et₃N/DCM 1.18 7 1.40 8 Pyridine/DCM 1.40

Example 5 Conditions Tested in the Preparation of Compound 6 in the Stepe

The conditions described in Table 3 below were tested in the step e inthe preparation of compound 6 from compound 5 providing a good yield ofcompound 6:

TABLE 3 Entry Solvent Base Temp. (° C.) Run time (h) 1 Toluene/ethanol6:4 K₂CO₃ 78 17 2 Toluene 3 Ethanol 4 2-propanol 5Toluene/2-propanol/water 3:2:1.8 6 2-MeTHF 7 Toluene/ethanol 6:4 50 8THF 9 2-MeTHF Et₃N 60 10 THF KOtBu

Example 6 Conditions Tested in the Preparation of Compound 7 in the Stepf

The conditions described in Table 4 below were tested in the step f inthe preparation of compound 7 from compound 6 providing a good yield ofcompound 7:

TABLE 4 Entry Condition Temp. (° C.) 1 Toluene/piperidine 74 2Ethanol/piperidine 74 3 Toluene/acetic acid/piperidine 74 4Methanol/piperidine 50

Example 7 Large Scale Synthesis of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionehydrochloride (9)

Steps d, e, f, g, and h refer to the steps described in the scheme ofExample 3 above. The ¹H-NMR spectra and the LC-MS data of the compoundsprepared were confirmed as described in Example 3.

Steps d and e: Synthesis of4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]-benzaldehyde(6)

To a well stirred solution of5-[[[(1,1-dimethylethyl)dimethylsilyl]-oxy]ethyl]-2-pyridineethanol (4)(obtained as described in Example 2) (8.14 kg) in toluene (33 L) at 5°C. were added sodium hydroxide (30% aqueous, 11.65 L) andtetrabutylammonium bromide (30.13 g). p-Toluenesulfonyl chloride (6.76kg) was next added, addition equipment rinsed with toluene (2 L) andrinse added to the reactor. After the addition, the reaction mixture wasallowed to reach room temperature and stirred at this temperatureovernight. Water (32 L) was then added and the mixture was mixed well.Once the solids were dissolved, the layers were allowed to settle andthe organic layer was separated. This organic phase was washed withwater twice (24 L, 2×). The solvents were evaporated partly at reducedpressure to yield a residue of 29.5 kg of a brown oil (compound 5).

To this well stirred brown oil were added ethanol (32 L), water (3.6 L),4-hydroxybenzaldehyde (3.69 kg) and potassium carbonate (4.87 kg) andthen the mixture was heated at 75° C. overnight. Next, toluene (32 L)was added and volatiles (32 L) were evaporated. Subsequent, the reactionmixture was allowed to cool. At 20° C., water (32 L) was added, stirreduntil all solids were dissolved and the mixture was cooled to roomtemperature. The layers were allowed to settle and separated. Theorganic layer was washed with water (32 L). The first aqueous extractwas extracted with toluene (12 L) and this organic extract was used toalso extract the aqueous washing. The organic extracts were combined andconcentrated under vacuum to give 15.6 kg of a black oil (crude titlecompound 6 containing residual toluene). This procedure was repeatedusing 8.14 kg of compound 4 to give another 13.3 kg of a black oil(crude title compound 6 containing residual toluene).

Both batches of crude compound 6 were pooled. 4.76 kg of this pooledblack oil was concentrated in vacuo, dissolved in ethanol (0.9 L) andadded to a well stirred solution of sodium bisulfite (7.3 L of a stocksolution prepared by dissolving 2.91 kg of sodium bisulfite in 10 L ofwater) and ethanol (1.1 L). The container of the black oil was rinsedwith ethanol (0.55 L 2×) twice and these two rinses were also added tothe bisulfite reaction mixture. After 75 min, heptane (8 L) was added,well mixed for 15 min, the layers were allowed to settle and separated.To the organic layer was added a solution of sodium bisulfite (2.8 L ofa stock solution prepared by dissolving 2.91 kg of sodium bisulfite in10 L of water), water (2.4 L) and ethanol (1.6 L). After stirring for 30min, the layers were allowed to settle and separated. The two bisulfideaqueous extracts were combined and flasks rinsed with water (3.2 L).Next, toluene (7 L) and heptane (7 L) were added, the mixture was wellstirred and the pH was adjusted to 12 using sodium hydroxide (10% aq)(temperature became 28° C.). After stirring for additional 20 min, thelayers were allowed to settle and separated at 30° C. The aqueous layerwas extracted with a mixture of toluene (2.3 L) and heptane (4.6 L). Thelayers were separated and the organic layers were combined. The combinedorganic layers were washed with water (7.7 L) and concentrated undervacuum to give the purified title compound 6 (4.17 kg containing 1.06 kgof toluene and 3.11 kg of compound 6). This procedure was repeated withthe remaining 24 kg of the black oil (crude title compound 6) and in tworuns gave in total an additional 14.23 kg of4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]-benzaldehyde(6) as brown oil corrected for residual of toluene (based on ¹H NMR) and0.13 kg of compound 6 as equipment rinse in methanol (total yield=79%,calculated from compound 4 and corrected for solvents).

Step f: Synthesis of(5Z)-5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione(7)

A solution of4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]-ethoxy]-benzaldehyde(6) (14.36 kg of compound 6 in toluene/methanol), toluene (22.2 L),piperidine (44 g) and methanol (14.5 L) was concentrated at 45° C.(jacket temperature) under reduced pressure. The residue was dissolvedin methanol (61.6 L) and 2,4-thiazolidinedione (5257 g) and piperidine(1544 g) were added. The addition equipment was rinsed with methanol (intotal 10.8 L), rinse also added to the reaction mixture and the mixturewas heated at 47° C. After 28 h, the reaction mixture was allowed tocool to room temperature. The pH mixture was adjusted to pH 5-6 byaddition of acetic acid (0.73 kg was required). After a night at roomtemperature, water (10.9 L) was added and the suspension was stirred atroom temperature for additional 2 h. The solids were isolated byfiltration, washed with methanol (7.3 L) and dried under vacuum to givecrude compound 7 (13.6 kg). The crude compound was mixed with methanol(16 L) and dichloromethane (54 L) and heated at 32° C. until all solidsdissolved. Then, solvent was removed by distillation under reducedpressure at jacket temperature of 45° C. keeping a constant volume byaddition of methanol until the temperature of the mixture reached 34° C.at a pressure of 333 mbar (84 L of distillate was removed and 84 L ofmethanol were added). Then, it was stirred at a setpoint jackettemperature of 2° C. for one hour. The solids were isolated byfiltration, washed with of methanol (8 L 2×) and dried under vacuum at30° C. to give title compound 7 (12.38 kg) (yield=68%).

Step g: Synthesis of5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(8)

To a stirred suspension of(5Z)-5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]-ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione(7) (12.38 kg) in THF (25 L) and sodium hydroxide (1N aq, 26 L) wasadded a solution of cobalt chloride (8.25 g) and of dimethylglyoxime(289 g) in THF (2.65 L) and water (0.66 L). The flask that contained thecobalt chloride/dimethylglyoxime was rinsed with a mixture of THF andwater (1/1 v/v, 1 L) and rinse added to the content of the reactor.Thereafter, the suspension was heated at 30° C. and put under a nitrogenatmosphere by applying the sequence of vacuum and flushing with nitrogen(4×). A stock solution of sodium borohydride was prepared by dissolvingsodium borohydride (5.0 kg) in a mixture of water (23.3 L) and asolution of sodium hydroxide (1 N aq, 6.2 L), which was put under anitrogen atmosphere by applying a sequence of vacuum and flushing withnitrogen (3×). This was added to the suspension of compound 7 at a rateof 6.0 L/h. Simultaneously, nitrogen gas-saturated acetic acid was addedto the suspension at such rate that a pH of 9.5-10.5 was maintained.After one hour the rate of addition of the sodium borohydride solutionwas reduced to 2.6 L/h. After addition of 23 L of sodium borohydridesolution the addition of sodium borohydride and acetic acid werestopped. The mixture was allowed to cool down to 20° C. and stirred atthis temperature overnight. Then acetone (3.1 L) was added slowly. Afterstirring the reaction mixture for 15 minutes, acetic acid was addeduntil the pH was 5.5-6.0 (5.2 L required). Next, a mixture of ethylacetate/toluene (1/3 v/v, 37.1 L) was added, well mixed and layers wereallowed to settle. The aqueous layer was separated and washed with ethylacetate/toluene (1/3 v/v, 12.4 L). Both organic extracts were pooled andwater (12.4 L) was added, well mixed and layers were allowed to settle.The pH of the aqueous layer was adjusted to 5.5-6 using a 1 M sodiumhydroxide solution (aq) and again mixed with the organic layer. Layerswere allowed to settle and the organic layer was separated andconcentrated under vacuum to give 23.15 kg of yellow oil (crude mixturecontaining title compound 8 and its borane complex and toluene). Theequipment was rinsed with toluene (4 L) to give a solution (4.7 kg)containing crude product in toluene.

The 23.15 kg of the crude mixture containing title compound 8 and itsborane complex and toluene and the rinse of 4.7 kg containing product intoluene were pooled, additional toluene (30 L) was added and stirred for30 minutes. Next, the suspension was filtered and solids were washedwith toluene (10 L). The filtrate was submitted to column chromatography(silica gel (70 kg), gradient of toluene to toluene/ethyl acetate 1/1)to give 18.7 kg of a toluene solution containing 10.96 kg of a mixtureof5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedione(8) and its borane complex as a slightly yellow oil (yield=85% fromcompound 7).

Step h: Synthesis of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedionehydrochloride (9)

A toluene solution of 18.7 kg containing 10.96 kg of a mixture of5-[[4-[2-[5-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione(8) and its borane complex was transferred to a reactor, containersrinsed with toluene (4 L) and rinse also added to the reactor. The levelof toluene was reduced to 25% w/w by distillation. Then it was dilutedwith methanol (54 L) at 20° C. and hydrochloric acid (30%, 6.15 L) wasadded in about 15 minutes. This solution was heated to 40° C. Two hoursafter addition, 40 L of volatiles were removed under reduced pressure.Then, acetonitrile (76 L) was added and the mixture was heated at refluxfor 0.5 h. Next, the suspension was allowed to cool down to roomtemperature and stirred for two hours at room temperature. Solids wereisolated by filtration, washed with a mixture of acetonitrile/water(20/1 v/v, 8.4 L), acetonitrile (14.5 L) and water (10 L). The isolatedsolids were transferred to a reactor, water (33 L) added, suspensionwell stirred and pH adjusted to 2 using 2M hydrochloric acid. Thesuspension was stirred at 50° C. for two hours and then allowed to coolto room temperature. After one hour at room temperature the solids wereisolated by filtration, washed with water (20 L) and dried under vacuumat 40° C. to give 7.77 kg of white solids (crude 9) (yield=85%, notcorrected for residual solvents).

Purification of5-[[4-[2-[5-(I-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionehydrochloride (9)

The crude5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidine-dionehydrochloride (7.77 kg, crude 9) was dissolved in a mixture of water (35L) and methanol (124 L) by beating. To this solution at 45° C. was addeda suspension of activated charcoal (0.78 kg) in methanol (4 L).Equipment was rinsed with methanol (38.4 L) and water (12.6 L) andrinses added to the reactor. After 0.5 h of stirring at 45° C., the warmsuspension was filtered to remove the activated charcoal and filter waswashed twice with methanol/water (7/2 v/v, 18 L). The filtrate wasconcentrated under vacuum at a jacket temperature of 50° C. to a volumeof 23.3 L. To the suspension was added butanone (38.9 L). Then volatileswere removed by distillation under simultaneously addition of butanoneat such rate that the volume was constant until a process temperature of76-77° C. was achieved (required 251 L of butanone). Next, heating wasstopped and the suspension was allowed to reach room temperature. After0.75 h at room temperature the solids were isolated by filtration,washed with a mixture of butanone/water (95/5 v/v, 38 L) and butanone(38 L), and dried under vacuum at 40° C. to give 7.14 kg of compound 9as white solid (yield=92%).

Example 8 Deuteration of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione

Deuteration of5-[[4-[2-[5-(I-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedionewas conducted as follows:

N,N-(Diisopropyl)aminomethylpolystyrene (1% inorganic agent) (PS-DIEA;3.2 eq) was added to a solution of5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedione(1.0 eq.) in CD₃OD (60 ml) and the mixture was stirred at roomtemperature for 7-8 days. The reaction mixture was filtered and washedwith CD₃OD (10 ml). The filtrate was concentrated, the residue wasdiluted with CH₂Cl₂ and concentrated completely to afford deuterated5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]-methyl]-2,4-thiazolidinedioneas a white solid (as a mixture of the 4 deuterated isomers). Yield: 73%(440 mg).

ES-MS [M+H]+: 374.1.

¹H NMR (400 MHz, DMSO-d₆): δ 11.98 (brs, 1H), 8.46 (d, J=1.6 Hz, 1H),7.67 (dd, J=8.0, 2.4 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.8 Hz,2H), 6.86 (d, J=8.4 Hz, 2H), 5.24 (d, J=4.4 Hz, 1H), 4.75 (m, 1H), 4.30(t, J=6.4 Hz, 2H), 3.31 (m, 1H), 3.14 (t, J=6.4 Hz, 2H), 3.03 (d, J=14.4Hz, 1H), 1.34 (d, J=6.4 Hz, 3H). Traces of undeuterated startingmaterial was observed.

Example 92-(5-(1-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-1-ol (4)

A 20 L flask equipped with mechanical stirrer, under nitrogenatmosphere, was charged with 3160 g (10.0 mol, 1.0 eq.) compound 3 and 8L of diethylether. The mixture was cooled to −60° C. and 4 L of 2.5Mn-BuLi in hexanes (10.0 mol, 1.0 eq. n-BuLi) was added dropwise within 1hour, while the temperature was kept <−55° C. The mixture was stirredfor 1 hour at −80° C. Copper(I)iodide (953 g, 5.0 mol, 0.5 eq.) wasadded at once, while the temperature was allowed to rise to −43° C. Themixture was cooled back to −55° C. to −60° C. A solution of ethyleneoxide (528 g, 12.0 mol, 1.2 eq.) in 900 g diethyl ether at −20° C.(prepared separately in a 2 L vessel) was added dropwise (quickly)within 20 minutes to the reaction-mixture. An exothermic reaction wasobserved and external cooling with liquid nitrogen was needed to keepthe temperature below −20° C. and finally to cool back to −60° C. Themixture was stirred overnight, while the reaction mixture was allowed toreach room temperature.

In a 40 L separation-vessel, 1.2 kg ammonium chloride was dissolved in 6L of water. The reaction-mixture was poured into the stirred ammoniumchloride-solution and stirred for 1 hour to destroy most of thecopper-complexes. The layers were separated and the water-layer wasextracted with heptane (2×2 L). The combined organic layers were driedover sodium sulfate and filtered over a Celite®-path (to remove morecopper-salts). After evaporation of the solvents 3088 g (max. 10.0 mol)crude compound 4 was isolated as a dark brown oil, which was purified bycolumn chromatography, using 22.5 Kg silica. A gradient was applied toelute the product, starting with 80 L heptane/EtOAc 1/I, followed by 20L EtOAc, 40 L EtOAc/MeOH 95/5, 20 L EtOAc/MeOH 9/1, 20 L EtOAc/MeOH 8/2and finally 40 L EtOAc/MeOH 7/3. The product fractions with high puritywere combined and evaporated to give 1390 g (4.94 mol, yield 9.4%)compound 4 as an brown oil with a HPLC-purity of 99.3%. The disclosurealso provides the following particular embodiments designated as [1] forthe first embodiment, [2] for the second embodiment, and so on:

[1] A process, comprising

reacting a compound of Formula II:

wherein PG is a protecting group selected from silyl protecting groups,tetrahydropyranyl, or methoxymethyl and LG¹ is a leaving group,with ethylene oxide in the presence of(a) an alkyl lithium and copper(I)iodide or(b) a Lewis acid selected from the group consisting of BF₃.O(Et)₂, BBr₃and BCl₃, and a solvent, whereinthe reaction temperature is maintained below −20° C.,to give a compound of Formula III:

[2] The process of [1], wherein PG is selected from silyl protectinggroups.

[3] The process of [1] or [2], wherein PG is an alkyl or aryl silylgroup, or a combination thereof.

[4] The process of any one of [1] to [3], wherein PG is a trialkylsilylgroup.

[5] The process of any one of [1] to [3], wherein PG is TBDMS, TMS, TES,TIPS, or TBDPS.

[6] The process of any one of [1] to [5], wherein PG istert-butyldimethylsilyl (TBDMS).

[7] The process of any one of [1] to [6], wherein LG is chloride,bromide, iodide, or fluoride.

[8] The process of any one of [1] to [7], wherein LG¹ is bromide.

[9] The process of any one of [1] to [8], wherein the reaction isconducted in the presence of an alkyl lithium and copper(I)iodide.

[10] The process of any one of [1] to [9], wherein the alkyl lithium andcopper(I)iodide are added while maintaining the reaction temperature atabout <−55° C.

[11] The process of any one of [1] to [10], wherein the alkyl lithium isn-butyllithium.

[12] The process of any one of [1] to [8], wherein the reaction isconducted in the presence of a Lewis acid selected from the groupconsisting of BF₃.O(Et)₂, BBr₃ and BCl₃.

[13] The process of any one of [1] to [12], wherein the solvent is anon-polar organic solvent.

[14] The process of any one of [1] to [13], wherein the solvent isdiethylether or tert-butyl ether.

[15] The process of any one of [1] to [12], wherein the solvent is apolar organic solvent.

[16] The process of any one of [1] to [12] and [15], wherein the solventis tetrahydrofuran.

[17] The process of any one of [1] to [16], further comprising isolatingsaid compound of Formula III and optionally purifying the isolatedcompound of Formula III.

[18] The process of any one of [1] to [17], further comprising reactingsaid compound of Formula III with R¹—Cl, wherein R¹ is anorganosulfonate, in the presence of a first base to give a compound ofFormula IV:

[19] The process of [18], wherein the organosulfonate is a tosyl group(Ts) or a mesyl group (Ms).

[20] The process of [18] or [19], wherein the organosulfonate is a tosylgroup.

[21] The process of any one of [18] to [20], wherein the first base isone or more of an amine, a quaternary ammonium salt,tetrabutylammoniumhydroxide, or an alkalimetal hydroxide.

[22] The process of any one of [18] to [21], wherein the first base is aquaternary ammonium salt, optionally in combination with a watersolution of an alkalimetal hydroxide.

[23] The process of [22], wherein the first base istetra-n-butylammonium bromide in aqueous NaOH.

[24] The process of any one of [18] to [23], wherein the reaction isconducted in the presence of a solvent.

[25] The process of any one of claims [18] to [24], further comprisingreacting said compound of Formula IV with 4-hydroxybenzaldehyde:

in the presence of a second base and a solvent to give a compound ofFormula V:

[26] The process of claim 25, wherein the second base is an alkali metalcarbonate, a trialkylamine, or an alkali metal alkoxide.

[27] The process of [25] or [26], wherein the second case is K₂CO₃.

[28] The process of any one of [25] to [27], wherein the solvent isselected from the group consisting of toluene, ethanol, 2-propanol, THF,2-MeTHF, and water, or a mixture thereof.

[29] The process of any one of [25] to [28], wherein the solvent is amixture of toluene and ethanol.

[30] The process of any one of [25] to [29], further comprising reactingsaid compound of Formula V with 2,4-thiazolidinedione:

in the presence of piperidine and optionally a solvent, and optionallyan organic acid, to give a compound of Formula VI:

[31] The process of [30], wherein the reaction is conducted in thepresence of the solvent.

[32] The process of [30] or [31], wherein the solvent is toluene, alower alcohol, hexane, or cyclohexane, or a mixture thereof.

[33] The process of any one of [30] to [32], wherein the solvent istoluene or methanol, or a mixture thereof.

[34] The process of any one of [30] to [33], wherein the reaction isconducted in the presence of the organic acid.

[35] The process of any one of [30] to [34], wherein the organic acid isacetic acid or formic acid.

[36] The process of any one of [30] to [35], wherein the reaction isconducted at a temperature of about 45° C. to about 80° C.

[37] The process of any one of [30] to [36], wherein the solvent ismethanol and the process is conducted at about 47° C.

[38] The process of any one of [30] to [37], further comprising reducingsaid compound of Formula VI to give a compound of Formula VII:

[39] The process of [38], wherein the reduction is conducted by allowingsaid compound of Formula VI to react with a reducing agent in thepresence of a metal ion and a complexing agent for the metal ion.

[40] The process of [38] or [39], wherein the reducing agent is NaBH₄.

[41] The process of any one of [38] to [40], wherein the metal ion isCo²⁺.

[42] The process of any one of [38] to [41], wherein the ligand isdimethylglyoxime.

[43] The process of any one of [38] to [42], further comprisingdeprotecting said compound of Formula VII, and optionally furthertreating with an acid, to give a compound of Formula I:

or a pharmaceutically acceptable salt thereof.

[44] The process of [43], wherein the deprotection of said compound odFormula VII and the salt formation are conducted in two separate steps.

[45] The process of [43], wherein the deprotection of said compound odFormula VII and the salt formation are conducted simultaneously.

[46] The process of any one of [43] to [45], wherein said compound ofFormula I is isolated as its pharmaceutically acceptable salt.

[47] The process of any one of [43] to [46], wherein said compound ofFormula I is5-[[4-[2-[5-(1-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedionehydrochloride salt.

[48] The process of [1], wherein said compound of Formula II is preparedby protecting the hydroxyl group of a compound of Formula VIII:

wherein LG¹ is a leaving group, with a protecting group PG, wherein PGis selected from silyl protecting groups, tetrahydropyranyl, ormethoxymethyl, to give the compound of Formula II.

[49] The process of [48], wherein said compound of Formula VIII reactedwith a silyl chloride selected from the group consisting of TBDMS-Cl,TMS-Cl, TBDPS-Cl, and TIPS-Cl and imidazole at high concentration inDMF.

[50] The process of [48] or [49], wherein said compound of Formula VIIIis prepared by reacting a compound of Formula IX:

wherein LG¹ is a leaving group, with CH₃CHO in the presence of analkylmagnesiumhalide and a solvent to give the compound of Formula VIII.

[51] A compound of Formula III:

wherein PG is a protecting group selected from silyl protecting groups,tetrahydropyranyl, or methoxymethyl, prepared by the process as in anyone of [1] to [17].

[52] A compound of Formula I:

or a pharmaceutically acceptable salt thereof, prepared by the processas in any one of [1] to [50].

It is to be appreciated that the Detailed Description section, and notthe Summary and Abstract sections, is intended to be used to interpretthe claims. The Summary and Abstract sections may set forth one or morebut not all exemplary embodiments of the present invention ascontemplated by the inventor(s), and thus, are not intended to limit thepresent invention and the appended claims in any way.

The present invention has been described above with the aid offunctional building blocks illustrating the implementation of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have been arbitrarily defined herein for the convenienceof the description. Alternate boundaries can be defined so long as thespecified functions and relationships thereof are appropriatelyperformed.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

1-109. (canceled)
 110. A process, comprising (i) combining an alkyllithium and a compound having Formula II:

in a solvent at a temperature from about −20° C. to about −85° C. togive a first reaction mixture, wherein PG is a protecting group and LG¹is bromide or iodide; (ii) adding ethylene oxide as is to said firstreaction mixture at said temperature to give a second reaction mixture;and (iii) adding a copper(I)salt to said second reaction mixture at saidtemperature to give a third reaction mixture comprising a compoundhaving Formula III:


111. The process of claim 110, wherein PG is a protecting group selectedfrom the group consisting of a silyl protecting group,tetrahydropyranyl, methoxymethyl, and benzyl.
 112. The process of claim111, wherein PG is selected from silyl protecting groups.
 113. Theprocess of claim 112, wherein PG is an alkyl or aryl silyl group, or acombination thereof.
 114. The process of claim 113, wherein PG is atrialkylsilyl group.
 115. The process of claim 114, wherein PG is TBDMS,TMS, TES, TIPS, or TBDPS.
 116. The process of claim 115, wherein PG istert-butyldimethylsilyl (TBDMS).
 117. The process of claim 110, whereinLG¹ is chloride.
 118. The process of claim 110, wherein LG¹ is bromide.119. The process of claim 110, wherein the alkyl lithium is C₁₋₆ alkyllithium.
 120. The process of claim 119, wherein the alkyl lithium isn-butyllithium.
 121. The process of claim 110, wherein the solvent isselected from the group consisting of a non-polar aprotic organicsolvent and a polar aprotic organic solvent, or a mixture thereof. 122.The process of claim 121, wherein the solvent is a non-polar aproticorganic solvent.
 123. The process of claim 122, wherein the solvent ismethyl tert-butyl ether.
 124. The process of claim 110, wherein saidthird reaction mixture is allowed to warm to a temperature of 20° C.-25°C.
 125. The process of claim 124, wherein said third reaction mixture iskept at 20° C.-25° C. for at least 4 hours, for at least 6 hours, for atleast 8 hours, or for at least 10 hours.
 126. The process of claim 110,further comprising isolating said compound of Formula III and optionallypurifying the isolated compound of Formula III.
 127. The process ofclaim 126, wherein the isolated compound of Formula III is purified byrecrystallization.